Indole derivatives having anti-angiogenetic activity

ABSTRACT

The invention relates to the use of a compound of Formula (I), for the manufacture of a medicament to inhibit and/or reverse and/or alleviate symptoms of angiogenesis and/or any disease state associated with angiogenesis: 
                         
wherein: X, p, q, R 1 , R 2 , R 3 , R 4 , and R 5  are as defined in the description. The invention also related to use of compounds of Formula (I) as medicaments and also to novel compounds of Formula (I). The invention further provides pharmaceutical compositions of compounds of Formula (I) and processes for the synthesis of compounds of Formula (I).

This application is a national stage filing under 35 U.S.C. 371 ofInternational Application No. PCT/GB03/01405, filed Mar. 31, 2003, whichclaims priority from European Patent Application No. 02290822.2, filedApr. 3, 2002, the specification of which is incorporated by referenceherein. International Application No. PCT/GB03/01405 was published underPCT Article 21(2) in English.

This invention relates to vascular damaging agents and their uses. Inparticular it relates to certain compounds which may be of use asvascular damaging agents, to methods for preparing the compounds, totheir use as medicaments (including methods for the treatment ofangiogenesis or disease states associated with angiogenesis) and topharmaceutical compositions containing them. The invention also relatesto the use of such compounds in the manufacture of medicaments for theproduction of anti-angiogenic and/or anti-vascular effects.

Normal angiogenesis plays an important role in a variety of processesincluding embryonic development, wound healing and several components offemale reproductive function. Undesirable or pathological angiogenesishas been associated with disease states including diabetic retinopathy,psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma andhaemangioma (Fan et al, 1995, Trends Pharmacol. Sci. 16: 57–66; Folkman,1995, Nature Medicine 1: 27–31). Formation of new vasculature byangiogenesis is a key pathological feature of several diseases (J.Folkman, New England Journal of Medicine 333, 1757–1763 (1995)). Forexample, for a solid tumour to grow it must develop its own blood supplyupon which it depends critically for the provision of oxygen andnutrients; if this blood supply is mechanically shut off the tumourundergoes necrotic death. Neovascularisation is also a clinical featureof skin lesions in psoriasis, of the invasive pannus in the joints ofrheumatoid arthritis patients and of atherosclerotic plaques. Retinalneovascularisation is pathological in macular degeneration and indiabetic retinopathy.

Reversal of neovascularisation by damaging the newly-formed vascularendothelium is therefore expected to have a beneficial therapeuticeffect. Such vascular-damaging activity would clearly be of value in thetreatment of disease states associated with angiogenesis such as cancer,diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma,haemangioma, acute and chronic nephropathies, atheroma, arterialrestenosis, autoimmune diseases, acute inflammation, endometriosis,dysfunctional uterine bleeding and ocular diseases with retinal vesselproliferation.

Certain known compounds that cause selective destruction of tumourvasculature have been reported, in vitro and at non-cytotoxicconcentrations, to cause effects on proliferating endothelial cells, ie,cell detachment [Blakey D C et al, Proceedings of the AmericanAssociation for Cancer Research, 41, 329, 2000 abstract 2086] andchanges in cell shape [Davis P D et al, Proceedings of the AmericanAssociation for Cancer Research, 41, 329, 2000 abstract 2085; Chaplin DJ & Dougherty G J, Br J Cancer, 80, Suppl 1, 57–64, 1999]. It cantherefore be expected that these compounds will have damaging effects onnewly-formed vasculature, for example the vasculature of tumours. It canreasonably be predicted, for example, that they will be capable ofcausing selective destruction of tumour vasculature, both in vitro andin vivo. Destruction of tumour vasculature in turn leads to a reductionin tumour blood flow and to tumour cell death due to starvation ofoxygen and nutrients, ie, to anti-tumour activity [Davis P D et al;Chaplin D J & Dougherty G J; Blakey D C et al, all supra].

Compounds with this activity have also been described in InternationalPatent Application WO 99/02166 (Angiogene Pharmaceuticals),International Patent Application WO00/40529 (Angiogene Pharmaceuticals)and International Patent Application WO 00/41669 (AngiogenePharmaceuticals).

We have identified a class of indole compounds with vascular damagingactivity. Thus, according to the first feature of the present inventionthere is provided the use of a compound of Formula (I), for themanufacture of a medicament to inhibit and/or reverse and/or alleviatesymptoms of angiogenesis and/or any disease state associated withangiogenesis

wherein:

-   R¹ is independently selected from halo, hydroxy, amino,    alkanoylamino, —OPO₃H₂, or C₁₋₄alkoxy, wherein the amino group is    optionally substituted by an amino acid residue and the hydroxy    group is optionally esterified;-   X is selected from: —O—, —S—, —SO— or —SO₂—;-   R² is selected from: hydrogen, C₁₋₄alkyl or C₁₋₄alkoxy;-   R³ and R⁴ are independently selected from: hydrogen, C₁₋₄alkyl,    C₁₋₄alkanoyl, C₁₋₄alkoxycarbonyl, C₁₋₄alkoxycarbonylC₁₋₄alkyl,    C₁₋₄alkoxycarbonylamino, amino, aminoC₁₋₄alkyl, carbamoyl,    carbamoylC₁₋₄alkyl, cyano, cyanoC₁₋₄alkyl, hydroxy,    hydroxyC₁₋₄alkyl, or a group of Formula (II):

-   R⁶ is hydrogen or C₁₋₄alkyl;-   R⁵ and R⁷ are independently selected from hydrogen, C₁₋₄alkyl or a    group of Formula (III):

-   -   wherein Y is selected from —NH—, —O— or a bond;        -   Z is selected from —NH—, —O—, —C(O)— or a bond;        -   r is an integer from 0 to 4;        -   t is an integer from 0 to 1;        -   R⁸ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, aryl, 5 or 6 membered            heterocyclyl, 5- or 6-membered heteroaryl, wherein aryl,            heteroaryl or heterocyclyl are optionally substituted by            C₁₋₄alkyl, C₁₋₄alkoxy, or a group of Formula (IV):

-   -   -   -   wherein n is an integer from 1 to 6, and;                -   R⁹ and R¹⁰ are independently selected from hydrogen,                    C₁₋₄alkyl or aryl; and

    -   p is an integer from 0 to 1; and

    -   q is an integer from 0 to 3;        with the proviso that:

-   (i) when R³ is cyano then R⁴ cannot be a group of Formula (II), and

-   (ii) when q is 0, R³ is cyano and X is —S— then R⁴ is other than    amino;

-   or a salt, pro-drug or solvate thereof.

According to a further aspect of the first feature of the inventionthere is provided the use of a compound of Formula (Ia), for themanufacture of a medicament to inhibit and/or reverse and/or alleviatesymptoms of angiogenesis and/or any disease state associated withangiogenesis:

wherein:

-   R¹ is independently selected from hydroxy, amino, alkanoylamino,    —OPO₃H₂, or C₁₋₄alkoxy, wherein the amino group is optionally    substituted by an amino acid residue and the hydroxy group is    optionally esterified;-   wherein: X, p, q, R², R³, R⁴, and R⁵ are as defined for Formula (I)    above;    with the proviso that:-   (i) when R³ is cyano then R⁴ cannot be a group of Formula (II), and    or a salt, pro-drug or solvate thereof.

According to a further aspect of the first feature of the inventionthere is provided a method of treatment, in a warm-blooded animal, toinhibit and/or reverse and/or alleviate symptoms of angiogenesis and/orany disease state associated with angiogenesis comprising administeringto said warm-blooded animal a therapeutically (includingprophylactically) effective amount of a compound of Formula (I) orFormula (Ia), or a pharmaceutically acceptable salt, pro-drug or solvatethereof.

Preferably a warm-blooded animal is a human.

A further feature of the invention provides a group of indole compoundsfor use in medicine. Thus, according to a second feature of the presentinvention there is provided the use of a compound of Formula (V) as amedicament, wherein:

-   R¹ is independently selected from halo, hydroxy, amino,    alkanoylamino, —OPO₃H₂, or C₁₋₄alkoxy, wherein the amino group is    optionally substituted by an amino acid residue and the hydroxy    group is optionally esterified;-   X is selected from: —O—, —S—, —SO— or —SO₂—;-   R² is selected from: hydrogen, C₁₋₄alkyl or C₁₋₄alkoxy;-   R³ and R⁴ are independently selected from: hydrogen, C₁₋₄alkyl,    C₁₋₄alkanoyl, C₁₋₄alkoxycarbonyl, C₁₋₄alkoxycarbonylC₁₋₄alkyl,    C₁₋₄alkoxycarbonylamino, amino, aminoC₁₋₄alkyl, carbamoyl,    carbamoylC₁₋₄alkyl, cyano, cyanoC₁₋₄alkyl, hydroxy,    hydroxyC₁₋₄alkyl; or a group of Formula (II):

-   R⁶ is hydrogen or C₁₋₄alkyl;-   R⁵ and R⁷ are independently selected from hydrogen, C₁₋₄alkyl or a    group of Formula (III):

-   -   wherein Y is selected from —NH—, —O— or a bond;        -   Z is selected from —NH—, —O—, —C(O)— or a bond;        -   r is an integer from 0 to 4;        -   t is an integer from 0 to 1;        -   R⁸ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, aryl, 5 or 6 membered            heterocyclyl, 5- or 6-membered heteroaryl, wherein aryl,            heteroaryl or heterocyclyl is optionally substituted by            C₁₋₄alkyl or C₁₋₄alkoxy, or a group of Formula (IV):

-   -   -   -   wherein n is an integer of from 1 to 6, and;                -   R⁹ and R¹⁰ are independently selected from hydrogen                    or C₄alkyl or aryl; and

    -   p is an integer from 0 to 1; and

    -   q is an integer from 0 to 3, preferably from 1 to 3;        with the proviso that

-   (i) when R³ is cyano then R⁴ cannot be a group of Formula (II);

-   (ii) when q is 0 and X is —S— then R³ is other than cyano;

-   (iii) when q is 0, p is 1, R² is hydrogen or 5-methoxy, R³ is    cyanomethyl and R⁴ is hydrogen or R³ is hydrogen and R⁴ is    cyanomethyl then R⁵ cannot be hydrogen methyl or acetyl;

-   (iv) when (R¹)_(q) is 4-methoxy, 4-amino or 3,4,5-trimethoxy, p is 0    or 1, R² is hydrogen or 5-methoxy, R³ is hydrogen, cyanomethyl or    2-aminoethyl, R⁴ is hydrogen or ethoxycarbonyl then R⁵ cannot be    hydrogen or methyl;

-   (v) when q is 0, p is 0 or 1, R² is hydrogen, 7-methyl, 5-methoxy or    6-methoxy, R³ is aminomethyl, 2-aminoethyl, 2-aminopropyl or    2-aminobutyl, R⁴ is hydrogen or methyl, then R⁵ cannot be hydrogen,    methyl, n-butyl or acetyl;

-   (vi) when q is 0, p is 0 or 1, R² is hydrogen, R³ is methyl, ethyl,    hydroxy, hydroxymethyl, 2-hydroxyethyl or 1-methylethoxy, R⁴ is    hydrogen, methyl, ethoxycarbonyl or tert-butoxycarbonyl or    carbamoyl, then R⁵ cannot be hydrogen, methyl or acetyl;

-   (vii) when q is 0, p is 0 or 1, R² is hydrogen or 5-methoxy, R³ is    hydrogen or bromo, R⁴ is hydrogen, methyl, methoxycarbonyl,    ethoxycarbonyl, tert-butoxycarbonyl or hydroxymethyl then R⁵ cannot    be methyl or n-butyl; and

-   (viii) when q is 0, p is 1, R² is hydrogen, 6-methyl, 7-methyl, or    5-methoxy, R³ is hydrogen, R⁴ is hydrogen, methoxycarbonyl,    ethoxycarbonyl, or 2-aminoethyl, then R⁵ cannot be hydrogen;    or a salt, pro-drug or solvate thereof;

According to a further aspect of the second feature of the inventionthere is provided a pharmaceutical composition comprising a compound ofFormula (V) or pharmaceutically-acceptable salt, pro-drug or solvatethereof.

According to a further aspect of the second feature of the inventionthere is provided a pharmaceutical composition comprising a compound ofFormula (V), or a pharmaceutically-acceptable salt, pro-drug or solvatethereof, in admixture with a pharmaceutically-acceptable diluent orcarrier.

The invention also provides a novel group of indole compounds. Thus,according to a third feature of the invention there is provided acompound of Formula (VI)

wherein:

-   R¹ is independently selected from halo, hydroxy, amino,    alkanoylamino, —OPO₃H₂, or C₁₋₄alkoxy, wherein the amino group is    optionally substituted by an amino acid residue and the hydroxy    group is optionally esterified;-   R² is selected from: hydrogen, C₁₋₄alkyl or C₁₋₄alkoxy;-   R³ and R⁴ are independently selected from: hydrogen, C₁₋₄alkyl,    C₁₋₄alkanoyl, C₁₋₄alkoxycarbonyl, C₄alkoxycarbonylC₁₋₄alkyl,    C₁₋₄alkoxycarbonylamino, amino, aminoC₁₋₄alkyl, carbamoyl,    carbamoylC₁₋₄alkyl, cyano, cyanoC₁₋₄alkyl, hydroxy,    hydroxyC₁₋₄alkyl; or a group of Formula (II):

-   R⁶ is hydrogen or C₁₋₄alkyl;-   R⁵ and R⁷ are independently selected from hydrogen, C₁₋₄alkyl or a    group of Formula (III):

-   -   wherein Y is selected from —NH—, —O— or a bond;        -   Z is selected from —NH—, —O—, —C(O)— or a bond;        -   r is an integer from 0 to 4;        -   t is an integer from 0 to 1;        -   R⁸ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, aryl, 5 or 6 membered            heterocyclyl, 5- or 6-membered heteroaryl, wherein aryl,            heteroaryl or heterocyclyl is optionally substituted by            C₁₋₄alkyl or C₁₋₄alkoxy, or a group of Formula (IV):

-   -   -   -   wherein n is an integer of from 1 to 6, and;                -   R⁹ and R¹⁰ are independently selected from hydrogen                    or C₁₋₄alkyl or aryl; and

    -   p is an integer from 0 to 1; and

    -   q is an integer from 0 to 3, preferably from 1 to 3;        with the proviso that

-   (i) when R³ is cyano then R⁴ cannot be a group of Formula (II);

-   (ii) when q is 0, p is 1, R² is hydrogen or 5-methoxy, R³ is    cyanomethyl and R⁴ is hydrogen or R³ is hydrogen and R⁴ is    cyanomethyl then R⁵ cannot be hydrogen methyl or acetyl;

-   (iii) when (R¹)_(q) is 4-methoxy, 4-amino, or 3,4,5-trimethoxy, p is    0 or 1, R² is hydrogen or 5-methoxy, R³ is hydrogen, cyanomethyl or    2-aminoethyl, R⁴ is hydrogen or ethoxycarbonyl then R⁵ cannot be    hydrogen or methyl;

-   (iv) when q is 0, p is 0 or 1, R² is hydrogen, 7-methyl, 5-methoxy    or 6-methoxy, R³ is aminomethyl, 2-aminoethyl, 2-aminopropyl or    2-aminobutyl, R⁴ is hydrogen or methyl, then R⁵ cannot be hydrogen,    methyl, n-butyl or acetyl;

-   (v) when q is 0, p is 1, R² is hydrogen, R³ is methyl, ethyl,    hydroxy, hydroxymethyl, 2-hydroxyethyl or 1-methylethoxy, R⁴ is    hydrogen, methyl, ethoxycarbonyl or tert-butoxycarbonyl or    carbamoyl, then R⁵ cannot be hydrogen, methyl or acetyl;

-   (vi) when q is 0, p is 1, R² is hydrogen or 5-methoxy, R³ is    hydrogen or bromo, R⁴ is hydrogen, methyl, methoxycarbonyl,    ethoxycarbonyl, tert-butoxycarbonyl or hydroxymethyl then R⁵ cannot    be methyl or n-butyl; and

-   (vii) when q is 0, p is 1, R² is hydrogen, 6-methyl, 7-methyl, or    5-methoxy, R³ is hydrogen, R⁴ is methoxycarbonyl, ethoxycarbonyl, or    2-aminoethyl, then R⁵ cannot be hydrogen;    or a salt, pro-drug or solvate thereof;

According to a further aspect of the third feature of the inventionthere is provided a compound of Formula (VIa)

wherein: p, q, R¹, R², R³, R⁴, and R⁵ are as defined for Formula (VI)above with the proviso that

-   (i) when R³ is cyano then R⁴ cannot be a group of Formula (II);-   (ii) when q is 0, p is 1, R² is hydrogen or 5-methoxy, R³ is    cyanomethyl and R⁴ is hydrogen or R³ is hydrogen and R⁴ is    cyanomethyl then R⁵ cannot be hydrogen;-   (iii) when q is 0, p is 1, R² is hydrogen or 5-methoxy, R³ is    aminomethyl, 2-aminoethyl, 2-aminopropyl, 2-aminobutyl,    methoxycarbonyl or methyl, R⁴ is hydrogen or methyl, then R⁵ cannot    be hydrogen, methyl or n-butyl; and-   (iv) when q is 0, p is 1, 2 is hydrogen or 5-methoxy, R³ is    hydrogen, R⁴ is hydrogen, methyl, hydroxymethyl or methoxycarbonyl    then R⁵ cannot be hydrogen, methyl or n-butyl.    or a salt, pro-drug or solvate thereof;

According to a further aspect of the third feature of the inventionthere is provided a compound of Formula (VIb)

-   wherein: p, q, R¹, R², R³, R⁴, and R⁵ are as defined for    Formula (VI) above    with the proviso that-   (i) when R³ is cyano then R⁴ cannot be a group of Formula (II);-   (ii) when (R¹)_(q) is 4-methoxy, p is 0, R² is hydrogen, R³ is    hydrogen, cyanomethyl or 2-aminoethyl R⁴ is hydrogen or    ethoxycarbonyl, then R⁵ cannot be hydrogen;-   (iii) when q is 0, p is 1, R² is hydrogen, R³ is cyanomethyl and R⁴    is hydrogen or R³ is hydrogen and R⁴ is cyanomethyl then R⁵ cannot    be hydrogen, methyl or acetyl;-   (iv) when q is 0, p is 0 or 1, R² is hydrogen, 6-methoxy or    7-methyl, R³ is 2-aminoethyl or 2-aminopropyl, R⁴ is hydrogen or    methyl, then R⁵ cannot be hydrogen, methyl or acetyl;-   (v) when q is 0, p is 1, R² is hydrogen, R³ is methyl, ethyl, bromo,    hydroxy, hydroxymethyl, 2-hydroxyethyl, 1-methylethoxy, acetyl,    ethoxycarbonyl or ethoxycarbonylethyl, R⁴ is hydrogen, methyl,    carbamoyl, ethoxycarbonyl or tert-butoxycarbonyl, then R⁵ cannot be    hydrogen or methyl; and-   (vi) when q is 0, R¹ is hydrogen, p is 1, R² is hydrogen, 6-methyl    or 7-methyl, R³ is hydrogen, R⁴ is hydrogen, ethoxycarbonyl or    2-aminoethyl, then R⁵ cannot be hydrogen or methyl;    or a salt, pro-drug or solvate thereof;

According to a further aspect of the third feature of the inventionthere is provided a compound of Formula (VIc)

-   wherein: p, q, R¹, R², R³, R⁴, and R⁵ are as defined for    Formula (VI) above    with the proviso that-   (i) when R³ is cyano then R⁴ cannot be a group of Formula (II);-   (ii) when (R¹)_(q) is 4-methoxy or 3,4,5-trimethoxy, p is 1, R² is    5-methoxy, R³ is hydrogen, cyanomethyl or 2-aminoethyl, R⁴ is    ethoxycarbonyl then R⁵ cannot be hydrogen; and-   (iii) when q is 0, p is 1, R² is hydrogen or 5-methoxy, R³ is    methyl, cyanomethyl, 2-aminoethyl, 2-aminopropyl or hydroxyethyl, R⁴    is hydrogen then R⁵ cannot be hydrogen.    or a salt, pro-drug or solvate thereof;

According to a further aspect of the third feature of the inventionthere is provided a compound of Formula (VId)

-   wherein: p, q, R¹, R², R³, R⁴, and R⁵ are as defined for    Formula (VI) above    with the proviso that-   (i) when R³ is cyano then R⁴ cannot be a group of Formula (II); and-   (ii) when q is 0 or (R¹)_(q) is 4-methoxy or 4-amino, p is 0 or 1 R³    is hydrogen or methyl, R⁴ is hydrogen or ethoxycarbonyl, then R⁵    cannot be hydrogen or methyl.    or a salt, pro-drug or solvate thereof.

According to a further aspect of the third feature of the inventionthere is provided a compound of Formula (VIe)

wherein:

-   R¹ is independently selected from hydroxy, amino, alkanoylamino,    —OPO₃H₂, or C₁₋₄alkoxy, wherein the amino group is optionally    substituted by an amino acid residue and the hydroxy group is    optionally esterified;-   wherein: q is from 1 to 3, and p, R², R³, R⁴, and R⁵ are as defined    for Formula (VI) above    with the proviso that-   (i) when R³ is cyano then R⁴ cannot be a group of Formula (II); and-   (ii) when (R¹)_(q) is 4-methoxy, 4-amino or 3,4,5-trimethoxy, p is 0    or 1, R² is hydrogen or 5-methoxy, R³ is hydrogen, cyanomethyl or    2-aminoethyl, R⁴ is hydrogen or ethoxycarbonyl, then R⁵ cannot be    hydrogen or methyl;    or a salt, pro-drug or solvate thereof.

According to a further aspect of the third feature of the inventionthere is provided a pharmaceutical composition comprising a compound ofFormula (VI), Formula (VIa), Formula (VIb), Formula (VIc), Formula (VId)or Formula (VIe) or pharmaceutically-acceptable salt, pro-drug orsolvate thereof.

According to a further aspect of the third feature of the inventionthere is provided a pharmaceutical composition comprising a compound ofFormula (VI), Formula (Via), Formula (VIb), Formula (VIc), Formula (VId)or Formula (VIe) or a pharmaceutically-acceptable salt, pro-drug orsolvate thereof, in admixture with a pharmaceutically-acceptable diluentor carrier.

According to a further aspect of the third feature of the presentinvention there is provided the use of a compound of Formula (VI),Formula (VIa), Formula (VIb), Formula (VIc), Formula (VId) or Formula(VIe), or pharmaceutically-acceptable salt, pro-drug or solvate thereoffor the manufacture of a medicament to inhibit and/or reverse and/oralleviate symptoms of angiogenesis and/or any disease state associatedwith angiogenesis.

According to a further aspect of the third feature of the inventionthere is provided a method of treatment, in a warm-blooded animal, toinhibit and/or reverse and/or alleviate symptoms of angiogenesis and/orany disease state associated with angiogenesis comprising administeringto said warm-blooded animal a therapeutically (includingprophylactically) effective amount of a compound of Formula (VI),Formula (Via), Formula (VIb), Formula (VIc), Formula (VId) or Formula(VIe), or a pharmaceutically acceptable salt, pro-drug or solvatethereof.

The invention also provides a further novel group of indole compounds.Thus, according to a fourth feature of the invention there is provided acompound of Formula (VII)

wherein:

-   R¹ is independently selected from halo, hydroxy, amino,    alkanoylamino, —OPO₃H₂, or C₁₋₄alkoxy, wherein the amino group is    optionally substituted by an amino acid residue and the hydroxy    group is optionally esterified;-   R² is selected from: hydrogen, C₁₋₄alkyl or C₁₋₄alkoxy;-   R³ and R⁴ are independently selected from: hydrogen, C₁₋₄alkyl,    C₁₋₄alkanoyl, C₁₋₄alkoxycarbonyl, C₁₋₄alkoxycarbonylC₁₋₄alkyl,    C₁₋₄alkoxycarbonylamino, amino, aminoC₁₋₄alkyl, carbamoyl,    carbamoylC₁₋₄alkyl, cyano, cyanoC₁₋₄alkyl, hydroxy,    hydroxyC₁₋₄alkyl; or a group of Formula (II):

-   R⁶ is hydrogen or C₁₋₄alkyl;-   R⁵ and R⁷ are independently selected from hydrogen, C₁₋₄alkyl or a    group of Formula (III):

-   -   wherein Y is selected from —NH—, —O— or a bond;        -   Z is selected from —NH—, —O—, —C(O)— or a bond;        -   r is an integer from 0 to 4;        -   t is an integer from 0 to 1;        -   R⁸ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, aryl, 5 or 6 membered            heterocyclyl, 5- or 6-membered heteroaryl, wherein aryl,            heteroaryl or heterocyclyl is optionally substituted by            C₁₋₄alkyl or C₁₋₄alkoxy, or a group of Formula (IV):

-   -   -   -   wherein n is an integer of from 1 to 6, and;                -   R⁹ and R¹⁰ are independently selected from hydrogen                    or C₁₋₄alkyl or aryl; and

    -   p is an integer from 0 to 1; and

    -   q is an integer from 0 to 3;        with the proviso that

-   (i) when R³ is cyano then R⁴ cannot be a amino or a group of Formula    (II);

-   (ii) when q is 0 or (R¹)_(q) is 4-amino, p is 0 or 1, R² is    hydrogen, R³ is hydrogen, R⁴ is hydrogen or ethoxycarbonyl, then R⁵    cannot be hydrogen;

-   (iii) when q is 0, p is 0 or 1, R² is hydrogen, R³ is hydrogen,    methyl, cyano, 2-aminoethyl, 1-methyl-2-aminoethyl or 2-aminopropyl,    R⁴ is hydrogen or amino, then R⁵ cannot be hydrogen; and

-   (iv) when q is 0, p is 0, R² is hydrogen, R⁴ is ethoxycarbonyl, then    R⁵ cannot be hydrogen;    or a salt, pro-drug or solvate thereof.

According to a further aspect of the fourth feature of the inventionthere is provided a compound of Formula (VIIa)

wherein:

-   wherein: p, q, R¹, R², R³, R⁴, and R⁵ are as defined for    Formula (VII) above    with the proviso that-   (i) when R³ is cyano then R⁴ cannot be a group of Formula (II);    or a salt, pro-drug or solvate thereof.

According to a further aspect of the fourth feature of the inventionthere is provided a compound of Formula (VIIb)

wherein:

-   wherein: p, q, R¹, R², R³, R⁴, and R⁵ are as defined for    Formula (VII) above    with the proviso that-   (i) when R³ is cyano then R⁴ cannot be a group of Formula (II); and-   (ii) when (R¹)_(q) is 4-chloro, p is 0, R² is hydrogen, R³ is    hydrogen, R⁴ is hydrogen or ethoxycarbonyl, then R⁵ cannot be    hydrogen;    or a salt, pro-drug or solvate thereof.

According to a further aspect of the fourth feature of the inventionthere is provided a compound of Formula (VIIc)

wherein:

-   X is selected from: —S—, —SO— or —SO₂—;-   R¹ is independently selected from hydroxy, amino, alkanoylamino,    —OPO₃H₂, or C₁₋₄alkoxy, wherein the amino group is optionally    substituted by an amino acid residue and the hydroxy group is    optionally esterified;-   q is an integer from 0 to 3, preferably from 1 to 3;-   and wherein: p, R², R³, R⁴, and R⁵ are as defined for Formula (VI)    above    with the proviso that-   (i) when R³ is cyano then R⁴ cannot be a group of Formula (II);-   (ii) when q is 0 or (R¹)_(q) is 4-amino, p is 0 or 1, R² is    hydrogen, R³ is hydrogen, R⁴ is hydrogen or ethoxycarbonyl, then R⁵    cannot be hydrogen;-   (iii) when q is 0, p is 0 or 1, R² is hydrogen, R³ is hydrogen,    methyl, cyano, 2-aminoethyl, 1-methyl-2-aminoethyl or 2-aminopropyl,    R⁴ is hydrogen or amino, then R⁵ cannot be hydrogen; and-   (iv) when q is 0, p is 0, R² is hydrogen, R⁴ is ethoxycarbonyl, then    R⁵ cannot be hydrogen;    or a salt, pro-drug or solvate thereof.

According to a further aspect of the fourth feature of the inventionthere is provided a compound of Formula (VIIe)

wherein:

-   X is selected from: —S—, —SO— or —SO₂—;-   R¹ is independently selected from hydroxy, amino, alkanoylamino,    —OPO₃H₂, or C₁₋₄alkoxy, wherein the amino group is optionally    substituted by an amino acid residue and the hydroxy group is    optionally esterified;-   q is an integer from 1 to 3;-   and wherein: p, R², R³, R⁴, and R⁵ are as defined for Formula (VI)    above    with the proviso that-   (i) when R³ is cyano then R⁴ cannot be a group of Formula (II); and-   (ii) when (R¹)_(q) is 4-amino, p is 0, R² is hydrogen, R³ is    hydrogen, R⁴ is hydrogen or ethoxycarbonyl, then R⁵ cannot be    hydrogen;    or a salt, pro-drug or solvate thereof.

According to a further aspect of the fourth feature of the inventionthere is provided a pharmaceutical composition comprising a compound ofFormula (VII), Formula (VIIa), Formula (VIb), Formula (VIc) or Formula(VIIe), or pharmaceutically-acceptable salt, or pro-drug solvatethereof.

According to a further aspect of the fourth feature of the inventionthere is provided a pharmaceutical composition comprising a compound ofFormula (VII), Formula (VIIa) Formula (VIIb), Formula (VIIc) or Formula(VIIe), or a pharmaceutically-acceptable salt, pro-drug or solvatethereof, in admixture with a pharmaceutically-acceptable diluent orcarrier.

According to a further aspect of the fourth feature of the presentinvention there is provided the use of a compound of Formula (VII),Formula (VIIa), Formula (VIIb), Formula (VIIc) or Formula (VIIe), orpharmaceutically acceptable salt, pro-drug or solvate thereof, for themanufacture of a medicament to inhibit and/or reverse and/or alleviatesymptoms of angiogenesis and/or any disease state associated withangiogenesis.

According to a further aspect of the fourth feature of the inventionthere is provided a method of treatment, in a warm-blooded animal, toinhibit and/or reverse and/or alleviate symptoms of angiogenesis and/orany disease state associated with angiogenesis comprising administeringto said warm-blooded animal a therapeutically (includingprophylactically) effective amount of a compound of Formula (VII),Formula (VIIa), Formula (VIIb), Formula (VIIc) or Formula (VIIe), or apharmaceutically acceptable salt, pro-drug or solvate thereof.

The invention also provides a further novel group of indole compounds.Thus, according to a fifth feature of the invention there is provided acompound of Formula (VIId)

wherein:

-   R¹ is independently selected from hydroxy, amino, alkanoylamino,    —OPO₃H₂, or C₁₋₄alkoxy, wherein the amino group is optionally    substituted by an amino acid residue and the hydroxy group is    optionally esterified;-   X is selected from: —O—, —S—, —SO— or —SO₂—;-   R² is selected from: hydrogen, C₁₋₄alkyl or C₁₋₄alkoxy;-   R³ and R⁴ are independently selected from: hydrogen, C₁₋₄alkyl,    C₁₋₄alkanoyl, C₁₋₄alkoxycarbonyl, C₁₋₄alkoxycarbonylC₁₋₄alkyl, C₄₋₁    alkoxycarbonylamino, amino, aminoC₁₋₄alkyl, carbamoyl,    carbamoylC₁₋₄alkyl, cyano, cyanoC₁₋₄alkyl, hydroxy,    hydroxyC₁₋₄alkyl; or a group of Formula (II):

-   R⁶ is hydrogen or C₁₋₄alkyl;-   R⁵ and R⁷ are independently selected from hydrogen, C₁₋₄alkyl or a    group of Formula (III):

-   -   wherein Y is selected from —NH—, —O— or a bond;        -   Z is selected from —NH—, —O—, —C(O)— or a bond;        -   r is an integer from 0 to 4;        -   t is an integer from 0 to 1;        -   R⁸ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, aryl, 5 or 6 membered            heterocyclyl, 5- or 6-membered heteroaryl, wherein aryl,            heteroaryl or heterocyclyl is optionally substituted by            C₁₋₄alkyl or C₁₋₄alkoxy, or a group of Formula (IV):

-   -   -   -   wherein n is an integer of from 1 to 6, and;                -   R⁹ and R¹⁰ are independently selected from hydrogen                    or C₁₋₄alkyl or aryl; and

    -   p is an integer from 0 to 1; and

    -   q is an integer from 1 to 3;        with the proviso that

-   (i) when R³ is cyano then R⁴ cannot be a group of Formula (II); and

-   (ii) when (R¹)_(q) is 4-methoxy, 4-amino, 4-chloro or    3,4,5-trimethoxy, p is 0 or 1, R² is hydrogen or 5-methoxy, R³ is    hydrogen, cyanomethyl or 2-aminoethyl, R⁴ is hydrogen or    ethoxycarbonyl, then R⁵ cannot be hydrogen or methyl;    or a salt, pro-drug or solvate thereof.

According to a further aspect of the fifth feature of the inventionthere is provided a pharmaceutical composition comprising a compound ofFormula (VIId), or pharmaceutically-acceptable salt, or pro-drug solvatethereof.

According to a further aspect of the fifth feature of the inventionthere is provided a pharmaceutical composition comprising a compound ofFormula (VIId), or a pharmaceutically-acceptable salt, pro-drug orsolvate thereof, in admixture with a pharmaceutically-acceptable diluentor carrier.

According to a further aspect of the fifth feature of the presentinvention there is provided the use of a compound of Formula (VIId), orpharmaceutically acceptable salt, pro-drug or solvate thereof, for themanufacture of a medicament to inhibit and/or reverse and/or alleviatesymptoms of angiogenesis and/or any disease state associated withangiogenesis.

According to a further aspect of the fifth feature of the inventionthere is provided a method of treatment, in a warm-blooded animal, toinhibit and/or reverse and/or alleviate symptoms of angiogenesis and/orany disease state associated with angiogenesis comprising administeringto said warm-blooded animal a therapeutically (includingprophylactically) effective amount of a compound of Formula (VIId), or apharmaceutically acceptable salt, pro-drug or solvate thereof.

Whilst pharmaceutically acceptable salts of compounds of the inventionare preferred, other non-pharmaceutically acceptable salts of compoundsof the invention may also be useful, for example in the preparation ofpharmaceutically-acceptable salts of compounds of the invention.

For the avoidance of doubt when q is 0, all positions on the phenyl ringare substituted by hydrogen.

For the avoidance of doubt the use of the term (R₁)_(q) when q is from 1to 3, means that there are 1, 2 or 3 R¹ substituents on the phenyl ring,which when q is 2 or 3 can be the same group or different groups. Forexample, where (R₁)_(q) is 3-chloro-4-methoxy then q is 2 and the phenylring has a chloro group at the 3-position and a methoxy group at the4-position, in relation to the —(CH₂)_(p)X— group, and for example, when(R₁)_(q) is di-halo, then q is 2 and the phenyl ring has two halosubstituents which may be the same group or different groups, whereinthe halo groups occupy 2 positions on the phenyl ring.

For the avoidance of doubt the use of the term (R₁)_(q-1) means there isone substituent on the phenyl ring as indicated in the respectiveformula and the phenyl ring can either bear no further substituents ormay bear one or two further substituents. Where there are two furthersubstituents these may the same group or different groups.

In this specification the generic term ‘alkyl’ includes bothstraight-chain and branched-chain alkyl groups. However references toindividual alkyl groups such as ‘propyl’ are specific for thestraight-chain version only and references to individual branched-chainalkyl groups such as ‘isopropyl’ are specific for the branched-chainversion only. An analogous convention applies to other generic terms.

The term “aryl” refers to phenyl or naphthyl.

The term “heteroaryl” refers to a 5–10 membered aromatic mono orbicyclic ring containing up to 5 heteroatoms independently selected fromnitrogen, oxygen or sulphur, linked via ring carbon atoms or ringnitrogen atoms where a bond from a nitrogen is allowed, for example nobond is possible to the nitrogen of a pyridine ring, but a bond ispossible through the 1-nitrogen of a pyrazole ring. Examples of 5- or6-membered heteroaryl ring systems include pyrrole, furan, imidazole,triazole, pyrazine, pyrimidine, pyridazine, pyridine, isoxazole,oxazole, 1,2,4 oxadiazole, isothiazole, thiazole and thiophene. A 9 or10 membered bicyclic heteroaryl ring system is an aromatic bicyclic ringsystem comprising a 6-membered ring fused to either a 5 membered ring oranother 6 membered ring. Examples of 5/6 and 6/6 bicyclic ring systemsinclude benzofuran, benzimidazole, benzthiophene, benzthiazole,benzisothiazole, benzoxazole, benzisoxazole, indole, pyridoimidazole,pyrimidoimidazole, quinoline, isoquinoline, quinoxaline, quinazoline,phthalazine, cinnoline and naphthyridine.

The term “heterocyclyl” refers to a 5–10 membered saturated or partiallysaturated mono or bicyclic ring containing up to 5 heteroatoms selectedfrom nitrogen, oxygen or sulphur linked via ring carbon atoms or ringnitrogen atoms. Examples of ‘heterocyclyl’ include pyrrolinyl,pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, dihydropyridinyland dihydropyrimidinyl

The term halo refers to fluoro, chloro, bromo or iodo.

The term “carbamoyl” refers to the group —C(O)—NH₂.

The term amino acid residue is defined as that derived from the couplingof an L-amino acid with an amino group via an amide bond. This bond caneither be formed via a carboxylate group on the amino acid backbone orvia a side chain carboxylate group, preferably via a carboxylate groupon the amino acid backbone. Amino acid residues include those derivedfrom natural and non-natural amino acids, preferably natural amino acidsand include α-amino acids β-amino acids and γ-amino acids. For theavoidance of doubt amino acids include those with the generic structure:

where R is the amino acid side chain: The definition of amino acid alsoincludes amino acid analogues which have additional methylene groupswithin the amino acid backbone, for example β-alanine and amino acidswhich are not naturally occurring such as cyclohexylalanine. Preferablyan animo acid residue is a naturally-occurring amino acid residue.

Preferred amino acids include glycine, alanine, valine, leucine,isoleucine, methionine, proline, phenylalanine, tryptophan, serine,threonine, cysteine, tyrosine, asparaginine, glutamine, aspartic acid,glutamic acid, lysine, arginine, histidine, β-alanine and ornithine.More preferred amino acids include glutamic acid, serine, threonine,arginine, glycine, alanine, β-alanine and lysine. Especially preferredamino acids include glutamic acid, serine, and glycine.

Esterifying groups at R¹ are esterifying groups which increase thesolubility of the molecule in water at a pH of approximately pH=7. Suchgroups include groups with ionisable groups, such as acidic functions orbasic functions and groups containing a hydrophilic function. Basicfunctions include: amino, morpholino, piperidino, piperazino,pyrrolidino, amino acids and imidazolino. Acidic functions include:carboxy, sulphonic acid, phosphate, sulphate and acid mimetics such astetrazolyl. Hydrophilic groups include hydroxyl.

Suitable R¹ groups wherein hydroxy is esterfied include:C₁₋₆alkanoyloxy, arylcarbonyloxy, heterocyclylcarbonyloxy,heteroarylcarbonyloxy wherein the R¹ group is optionally substitutedwith from 1 to 3 groups selected from C₁₋₄alkyl, C₁₋₄alkanoyl,C₁₋₄alkanoylC₁₋₄alkyl, C₁₋₄alkanoylheterocyclyl, hydroxy,hydroxyC₁₋₄alkyl, carboxy, carboxyphenyl, phosphono, phosphonoC₁₋₄alkyl,amino, aminoC₁₋₄alkyl, N—C₁₋₄alkylamino, N,N-diC₁₋₄alkylamino,carbamoyl, carbamoylC₁₋₄alkyl, heterocyclyl, heterocyclylC₁₋₄alkyl,heterocyclylcarbonyl, heterocyclC₁₋₄alkanoylamino,carbamoylheterocyclyl, [wherein optional substituents comprisingheterocyclyl are optionally further substituted by C₁₋₄alkyl,hydroxyC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkanoyl and formyl, whereinthe carbamoyl and amino optional substituents are optionally furtherN-substituted by C₁₋₄alkyl, di-C₁₋₄alkyl, hydroxyC₁₋₄alkyl,di-(hydroxyC₁₋₄alkyl), carboxyC₁₋₄alkyl, and wherein the amino group isoptionally substituted by an amino acid residue] with the proviso thatwhen R₁ is C₁₋₆alkanoyloxy or arylcarbonyloxy R₁ is not unsubstitutedand R₁ is not substituted by C₁₋₄alkyl.

More preferred R¹ groups wherein hydroxy is esterfied include:carboxypentanoyloxy, 4-carboxyphenylpropanoyloxy;4-(N-methylpipeaizin-1-ylethyl)phenylcarbonyloxy,4-(piperazin-1-ylethyl)phenylcarbonyloxy,4-[N-di-(hydroxyethyl)aminomethyl]phenylcarbonyloxy,3-(N-acetylpiperazin-1-ylethyl)phenylcarbonyloxy,3-[N-di-(hydroxyethyl)aminomethyl]phenylcarbonyloxy,4-(N-methylpiperazin-1-ylpropanoylamino)phenylcarbonyloxy,N-methylpiperazin-1-ylcarbonylpropanoyloxy,N-di-(hydroxyethyl)aminocarbonylpropanoyloxy,piperazin-1-ylcarbonylpropanoyloxy,(N-acetylpiperazin-1-yl)carbonylpropanoyloxy,(N-di-(hydroxyethyl)aminocarbonylpropanoyloxy, and4-(piperazin-1-ylmethyl)phenylcarbonyloxy.

Further preferred R¹ groups wherein hydroxy is esterfied include:4-(N-methylpiperazin-1-ylpropanoylamino)phenylcarbonyloxy,N-methylpiperazin-1-ylcarbonylpropanoyloxy andN-di-(hydroxyethyl)aminocarbonylpropanoyloxy.

Examples of C₁₋₄alkyl include methyl, ethyl, propyl, isopropyl,sec-butyl and tert-butyl; examples of C₁₋₄alkoxy include methoxy,ethoxy, propoxy and tert-butoxy; examples of C₁₋₄alkanoyl includeacetyl, propanoyl and butanoyl; examples of C₁₋₄alkanoylamino includeacetylamino, propanoylamino and butanoylamino; examples ofC₁₋₄alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl andtert-butyloxycarbonyl; examples of C₁₋₄alkoxycarbonylC₁₋₄alkyl includemethoxycarbonylethyl, ethoxycarbonylmethyl andtert-butyloxycarbonylbutyl; examples of C₁₋₄alkoxycarbonylamino includemethoxycarbonylamino, ethoxycarbonylamino andtert-butyloxycarbonylamino; examples of aminoC₁₋₄alkyl includeaminomethyl, aminoethyl and aminopropyl; examples of cyanoC₁₋₄alkylinclude cyanomethyl, cyanoethyl and cyanopropyl; examples ofcarbamoylC₁₋₄alkyl include carbamoylmethyl, carbamoylethyl andcarbamoylpropyl; examples of hydroxyC₁₋₄alkyl include hydroxymethyl,hydroxyethyl and hydroxypropyl.

It is to be understood that, insofar as certain of the compounds in thedifferent features of the invention may exist in optically active orracemic forms by virtue of one or more asymmetric carbon atoms, theinvention includes in its definition any such optically active orracemic form which possesses the property of inhibiting and/or reversingand/or alleviating the symptoms of angiogenesis and/or any diseasestates associated with angiogenesis. The synthesis of optically activeforms may be carried out by standard techniques of organic chemistrywell known in the art, for example by synthesis from optically activestarting materials or by resolution of a racemic form. Similarly,activity of these compounds may be evaluated using the standardlaboratory techniques referred to hereinafter.

The invention also relates to any and all tautomeric forms of thecompounds of the different features of the invention that possess theproperty of inhibiting and/or reversing and/or alleviating the symptomsof angiogenesis and/or any disease states associated with angiogenesis.

It will also be understood that certain compounds of the presentinvention may exist in solvated, for example hydrated, as well asunsolvated forms. It is to be understood that the present inventionencompasses all such solvated forms which possess the property ofinhibiting and/or reversing and/or alleviating the symptoms ofangiogenesis and/or any disease states associated with angiogenesis.

A suitable pharmaceutically-acceptable salt of a compound of theinvention is, for example, an acid-addition salt of a compound of theinvention which is sufficiently basic, for example, an acid-additionsalt with, for example, an inorganic or organic acid, for examplehydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic,citric or maleic acid. In addition a suitablepharmaceutically-acceptable salt of a carbazole derivative of theinvention which is sufficiently acidic is an alkali metal salt, forexample a sodium or potassium salt, an alkaline earth metal salt, forexample a calcium or magnesium salt, an ammonium salt or a salt with anorganic base which affords a physiologically acceptable cation, forexample a salt with methylamine, dimethylamine, trimethylamine,piperidine, morpholine or tris-(2-hydroxyethyl)amine.

A preferred group of values of R¹ in each feature of the invention ishydroxy, amino, —OPO₃H₂, or C₁₋₄alkoxy, wherein the amino group isoptionally substituted by an amino acid residue and the hydroxy group isoptionally esterified. A further preferred group of values of R¹ in eachfeature of the invention is hydroxy, amino, —OPO₃H₂, or C₁₋₄alkoxy,wherein the amino group is optionally substituted by an amino acidresidue. A more further preferred group of values of R¹ in each featureof the invention is hydroxy, amino, —OPO₃H₂, methoxy, ethoxy,glutamylamino preferably α-glutamylamino, serylamino, glycylamino oralanylamino. A yet more further preferred group of values of R¹ in eachfeature of the invention is hydroxy, α-glutamylamino, seryl, —OPO₃H₂ ormethoxy. A most preferred group of values of R¹ in each feature of theinvention is 3,4-dimethoxy, 3,5-dimethoxy, 2,5-dimethoxy,3,4,5-trimethoxy, 4-hydroxy-3,5-dimethoxy or4-phosphonooxy-3,5-dimethoxy.

A preferred group of values in each feature of the invention for p is 0or 1. More preferably in each features of the invention p is 0.

A preferred group of values in each feature of the invention for q is 2or 3. More preferably in each features of the invention q is 3.

A preferred group of values of X in the first and second features of theinvention is —O—, —S— or —SO₂—. Most preferably X is —S—.

A preferred group of values for R² in each feature of the invention ishydrogen.

A preferred group of values for R³ in each feature of the invention ishydrogen, C₁₋₄alkanoyl, C₁₋₄alkoxycarbonyl, hydroxyC₁₋₄alkyl, carbamoylor C₁₋₄alkylcarbamoyl, A more preferred group of values for R³ in eachfeature of the invention is cyano, C₁₋₄alkylcyano, carbamoyl orC₁₋₄alkylcarbamoyl. A most preferred group of values for R³ in eachfeature of the invention is C₁₋₄alkylcyano or cyano.

A preferred group of values for R⁴ in each feature of the invention ishydrogen, carbamoyl, carbamoylC₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl,cyano or a group of Formula (II). A more preferred group of values forR⁴ is hydrogen, cyano, carbamoyl, carbamoylC₁₋₄alkyl, C₁₋₄alkoxy orC₁₋₄alkoxycarbonyl. A most preferred value for R⁴ is hydrogen.

A preferred group of values for R⁵ in each aspect of the invention ishydrogen, C₁₋₄alkyl or a group of Formula (III) wherein t, Y, r, Z andR⁸ are as defined above. A more preferred group of values for R⁵ in eachaspect of the invention is hydrogen or C₁₋₄alkyl. A further preferredvalue for R⁵ is hydrogen, methyl or ethyl. A most preferred value for R⁵is methyl.

A preferred group of values for R⁶ in each aspect of the invention ishydrogen or C₁₋₄alkyl. More preferably R⁶ is hydrogen or methyl. Mostpreferably R⁶ is hydrogen.

A preferred group of values for R⁷ in each aspect of the invention ishydrogen, methyl, or a group of Formula (III). A most preferred group ofvalues for R⁷ is hydrogen or a group of Formula (III). A most preferredvalue of R⁷ is hydrogen.

A preferred group of values for t in each aspect of the invention is 0or 1. A most preferred value for t in each aspect of the invention is 0.

A preferred group of values for Y in each aspect of the invention is ora bond. A most preferred group of values for Y in each aspect of theinvention is —O—.

A preferred group of values for r in each aspect of the invention is 1,2 or 3. A most preferred values for r in each aspect of the invention is1.

A preferred group of values for Z in each aspect of the invention is—C(O)— or a bond. A most preferred group of values for Z in each aspectof the invention is a bond.

A preferred group of values for R⁸ in each aspect of the invention ishydrogen, C₄alkyl C₁₋₄alkoxy, an aryl group, a 6-membered heterocyclicgroup or a group of Formula (IV), wherein the aryl group andheterocyclic group are optionally substituted by C₁₋₄alkyl orC₁₋₄alkoxy: More preferably R⁸ is a non-aromatic heterocyclic group, anaryl group or a group of Formula (IV), wherein the aryl group andnon-aromatic heterocyclic group are optionally substituted by C₁₋₄alkylor C₁₋₄alkoxy. Further preferably R⁸ is phenyl, morpholino, piperazinylor a group of Formula (IV), wherein the phenyl, morpholino andpiperazinyl group are optionally substituted by methyl or acetyl and R⁹and R¹⁰ are both hydrogen. Most preferably R⁸ is phenyl, morpholino or4-methyl-piperazin-1-yl.

A preferred group of values for n in each aspect of the invention is 2or 3. Preferably n is 2.

A preferred group of values for R⁹ and R¹⁰ in each aspect of theinvention is R⁹ and R¹⁰ are independently selected from hydrogen or analkaryl group, preferably —(CH₂)_(m)—Ph where m is an integer of from 1to 6, preferably m is 1. More preferably R⁹ and R¹⁰ are independentlyselected from hydrogen or benzyl (—CH₂—Ph). Preferably R⁹ and R¹⁰ areboth hydrogen.

A preferred group of values for a group of Formula (III) isphenoxycarbonyl, phosphonooxyethylaminocarbonyl,4-methylpiperazin-1-ylpropoxycarbonyl, carbamoylmethyl,4-acetyl-piperazin-1-ylethoxycarbonyl,4-methyl-piperazin-1-ylcarbonylpropanoyl and morpholinoethoxycarbonyl.Preferably phenoxycarbonyl, 4-methylpiperazin-1-ylpropoxycarbonyl orcarbamoylmethyl.

Preferably only one of R⁵ and R⁷ is a group of Formula (III).

In the following preferred groups of compounds of each aspect of theinvention values for R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, n, p, q,r, t, X, Y and Z are as hereinbefore defined, unless specificallydefined with a preferred group of compounds.

A preferred group of compounds in the first and second features of theinvention; comprise compounds wherein:

-   X is —O—;    or salt, pro-drug or solvate thereof.

A preferred group of compounds in the first and second features of theinvention; comprise compounds wherein:

-   X is —S—, —SO— or —S(O)₂—;    or salt, pro-drug or solvate thereof.

A further preferred group of compounds in each feature of the invention,comprise compounds wherein:

-   R³ is selected from cyano or cyanoC₁₋₄alkyl, preferably cyano;    or salt, pro-drug or solvate thereof.

A further preferred group of compounds of each feature of the invention;comprise compounds wherein:

-   R¹ is amino, hydroxy or —OPO₃H₂, wherein the amino group is    optionally substituted by an amino acid residue and the hydroxy    group is optionally esterified;    or salt, pro-drug or solvate thereof.

A further preferred group of compounds of each feature of the invention,comprise compounds wherein:

-   R¹ is independently selected from hydroxy, amino, —OPO₃H₂, or    C₁₋₄alkoxy, wherein the amino group is optionally substituted by an    amino acid residue and the hydroxy group is optionally esterified;-   R³ is selected from carbamoyl, carbamoylC₁₋₄alkyl, cyano or    cyanoC₁₋₄alkyl; preferably cyano or cyanoC₁₋₄alkyl; and-   R⁵ is hydrogen or C₁₋₄alkyl;    or salt, pro-drug or solvate thereof.

A further preferred group of compounds of the first and second featuresof the invention, comprise compounds wherein:

-   R¹ is independently selected from hydroxy, amino, —OPO₃H₂, or    C₁₋₄alkoxy, wherein the amino group is optionally substituted by an    amino acid residue and the hydroxy group is optionally esterified;-   X is —S— or —O—;-   R³ is selected from carbamoyl, carbamoylC₁₋₄alkyl, cyano or    cyanoC₁₋₄alkyl; preferably cyano or cyanoC₁₋₄alkyl; and-   R⁵ is hydrogen or C₁₋₄alkyl;    or salt, pro-drug or solvate thereof.

A further preferred group of compounds in each feature of the invention,comprise compounds wherein:

-   R¹ is independently selected from hydroxy, —OPO₃H₂, or C₁₋₄alkoxy;-   R³ is selected from carbamoyl, carbamoylC₁₋₄alkyl, cyano or    cyanoC₁₋₄alkyl; preferably cyano or cyanoC₁₋₄alkyl; and-   R⁵ is hydrogen or C₁₋₄alkyl;    or salt, pro-drug or solvate thereof.

A further preferred group of compounds of the first and second featuresof the invention, comprise compounds wherein:

-   R¹ is independently selected from hydroxy, —OPO₃H₂, or C₁₋₄alkoxy;-   X is —S— or —O—;-   R³ is selected from carbamoyl, carbamoylC₁₋₄alkyl, cyano or    cyanoC₁₋₄alkyl; preferably cyano or cyanoC₁₋₄alkyl; and-   R⁵ is hydrogen or C₁₋₄alkyl;    or salt, pro-drug or solvate thereof.

A further preferred group of compounds in each feature of the invention,comprise compounds wherein:

-   R¹ is selected from hydroxy-dimethoxy, trimethoxy or    phosphonooxy-dimethoxy; preferably 3,4-dimethoxy, 3,5-dimethoxy,    2,5-dimethoxy, 3,4,5-trimethoxy, 4-hydroxy-3,5-dimethoxy or    4-phosphonooxy-3,5-dimethoxy;-   R³ is selected from carbamoyl, carbamoylC₁₋₄alkyl, cyano or    cyanoC₁₋₄alkyl; preferably cyano or cyanoC₁₋₄alkyl; and-   R⁵ is hydrogen or C₁₋₄alkyl;    or salt, pro-drug or solvate thereof.

A further preferred group of compounds of the first and second featuresof the invention, comprise compounds wherein:

-   R¹ is selected from hydroxy-dimethoxy, trimethoxy or    phosphonooxy-dimethoxy; preferably 3,4-dimethoxy, 3,5-dimethoxy,    2,5-dimethoxy, 3,4,5-trimethoxy, 4-hydroxy-3,5-dimethoxy or    4-phosphonooxy-3,5-dimethoxy;-   X is —S— or —O—;-   R³ is selected from carbamoyl, carbamoylC₁₋₄alkyl, cyano or    cyanoC₁₋₄alkyl; preferably cyano or cyanoC₁₋₄alkyl; and-   R⁵ is hydrogen or C₁₋₄alkyl;    or salt, pro-drug or solvate thereof.

A further preferred group of compounds of the first and second featuresof the invention comprise compounds, wherein:

-   R¹ is selected from hydroxy, amino, —OPO₃H₂, or C₁₋₄alkoxy, wherein    the amino group is optionally substituted by an amino acid residue;-   R² is hydrogen;-   X is selected from: —O—, or —S—;-   p is 0 or 1;-   q is an integer from 1 to 3;-   R³ is selected from: hydrogen, cyano, carbamoyl, carbamoylC₁₋₄alkyl,    C₁₋₄alkanoy, C₁₋₄alkoxycarbonyl;-   R⁴ is selected from: hydrogen, cyano or carbamoyl;-   R⁵ is hydrogen or C₁₋₄alkyl    or salt, pro-drug or solvate thereof.

Particular compounds of each feature of the invention include:

-   -   3-cyano-5-phenylsulphanyl-1H-indole;    -   3-cyano-5-phenoxy-1H-indole;    -   3-cyano-5-(4-hydroxyphenoxy)-1H-indole;    -   2-cyano-5-benzyloxy-1H-indole;    -   3-Carbamoyl-5-phenoxy-1H-indole; and    -   3-Carbamoyl-5-(4-hydroxyphenoxy)-1H-indole.        or salt, pro-drug or solvate thereof

More particular compounds of each feature of the invention include:

-   -   1-methyl-3-cyano-5-(4-hydroxy-3,5-dimethoxyphenoxy)-1H-indole;    -   1-methyl-3-cyano-5-(4-phosphonoxy-3,5-dimethoxyphenoxy)-1H-indole;    -   3-cyano-5-(3,4-dimethoxyphenylsulphanyl)-1H-indole;    -   1-methyl-3-cyano-5-(3,4-dimethoxyphenylsulphanyl)-1H-indole; and    -   1-Methyl-3-cyano-5-(4-hydroxy-3,5-dimethoxyphenoxy)-1H-indole.        or salt, pro-drug or solvate thereof

A compound of the invention or a pharmaceutically-acceptable salt, orsolvate thereof, may be prepared by any process known to be applicableto the preparation of chemically related compounds. Such processes, whenused to prepare a compound of the invention or apharmaceutically-acceptable salt, or solvate thereof, are provided as afurther feature of the invention and are illustrated by the followingrepresentative examples in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹,R¹⁰, X, Y, Z, n, p, q, r and t have the same meaning as herein beforedefined. The reader is referred to Advanced Organic Chemistry, 4^(th)Edition, by Jerry March, published by John Wiley & Sons 1992, forgeneral guidance on reaction conditions and reagents. The reader isreferred to Protective Groups in Organic Synthesis 2^(nd) Edition, byGreen et al, published by John Wiley & Sons for general guidance onprotecting groups.

Thus, according to the sixth aspect of the invention there is provided aprocess for preparing a compound of Formula (I), or salt, solvate orpro-drug thereof, which process (wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁰, R¹¹, X, Y, Z, n, p, q, r and t are unless otherwise specifiedas defined in Formula (I)) comprising:

-   a) for compounds of Formula (I) wherein X is —O—, or —S—, reacting a    compound of Formula (A) with a compound of Formula (B),

-    wherein L¹ is a leaving group;-   b) for compounds of Formula (I) in which R¹ comprises amino,    reduction of a compound of Formula (C):

-   c) for compounds of Formula (I) wherein R⁵ is C₁₋₄alkyl, reacting a    compound of Formula (I) wherein R⁵ is hydrogen with a suitable    alkylhalide,-   d) for compounds of Formula (I) wherein R¹ comprises an amino group    substituted by an amino acid residue, reacting a compound of    Formula (D) with an amino acid,

-   e) for compounds of Formula (I) in which R³ is a group of    Formula (II) and R⁷ is a group of Formula (III), reacting a    compounds of Formula (I) in which R³ is a group of Formula (II) and    R⁷ is hydrogen with compounds of Formula (E) below, in which L² is a    leaving group:

-   f) for compounds of Formula (I) in which R⁴ is hydrogen, reacting a    compounds of Formula (I) in which R³ is hydrogen and R⁴ is hydrogen    with a compounds of L³R³ in which L³ is a leaving group;-   g) for compounds of Formula (I) in which R¹ is an esterified    hydroxyl group, reacting a compound of Formula (F) with an    appropriate carboxylic acid or carboxylic acid derivative;

and thereafter if necessary:

-   i) converting a compound of Formula (I) into another compound of    Formula (I);-   ii) removing any protecting groups;-   iii) forming a salt, pro-drug or solvate.

According to a further feature of the sixth aspect of the inventionthere is provided the processes a), b), c), d), e), f) and g) describedabove for the preparation of compounds of the Formula (I), or a salt,pro-drug or solvate thereof.

Specific reaction conditions for the above reactions are as follows:

-   Process a) Compounds of Formula (A) and compound of Formula (B) can    be reacted together in an organic solvent, at a temperature between    room temperature and about 80° C., optionally in the presence of a    base such as sodium hydride, potassium carbonate or triethylamine.-   Process b) The conditions for reduction of a compound of Formula (C)    are well known in the art. Examples of reducing agents include    hydrogen and a hydrogenation catalyst (for example palladium on    carbon), iron and acetic acid, and zinc and hydrochloric acid. The    reaction is preferably carried out in the presence of a suitable    solvent such as an alcohol, for example methanol or ethanol, and at    a temperature in the range of 0–80° C., preferably at or near room    temperature. Further examples of reducing conditions include sodium    dithionite in the presence of a base, preferably sodium bicarbonate    in a suitable solvent such as DMF or N-methyl-pyrrolidone.

Compounds of Formula (C) can be prepared by reaction of a compound ofFormual (F) and a compound of Formula (G) as described in process a).

-   Process c) Compounds of Formula (I) wherein R₂ is hydrogen and a    suitable alkyl halide may be reacted together in a suitable organic    solvent such as DMF or DMSO, in the presence of a base, such as    sodium hydride or potassium carbonate at a temperature between about    room temperature and about 80° C.-   Process d) Compound of Formula (D) can be reacted with an amino acid    using a suitable amide bond forming reaction. Amide bond forming    reactions are well known in the art, for example, a carbodiimide    coupling reaction can be performed with EDAC in the presence of DMAP    in a suitable solvent such as methylene chloride, chloroform or DMF    at room temperature.-   Process e) Compounds of Formula (I) in which R³ is hydrogen can be    reacted with compounds of Formula (E) under conditions well known in    the art. For example L² may be chloro or p-nitrophenoxy. When L² is    Chloro this is carried out in the presence of a base, preferably    pyridine.-   Process f) Compounds of Formula (I) in which R³ is hydrogen and R⁴    is hydrogen can be reacted with compounds of the formula L³R³ in    acetonitrile or diethyl ether in the presence of a base such as    triethylamine at a temperature between 0° C. and room temperature;-   Process g) Processes for the formulation of an ester between a    hydroxyl group and a carboxylic acid or carboxylic acid derivative    are well know in the art. For example this reaction an acid chloride    can be reacted with an alcohol in the presence of a base such as    triethylemaine. A carboxylic acid derivative is any derivative of a    carboxylic acid which when reacted with a hydroxyl under appropriate    conditions will form an ester bond. Examples of carboxylic acid    derivatives include an acid chloride.

The compounds used as starting points for the reactions described aboveare commercially available or they are known compounds or they areprepared by processes known in the art.

It will also be appreciated that in some of the reactions mentionedherein it may be necessary/desirable to protect any sensitive groups inthe compounds. The instances where protection is necessary or desirableand suitable methods for protection are known to those skilled in theart. Conventional protecting groups may be used in accordance withstandard practice (for illustration see T. W. Green, Protective Groupsin Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactantsinclude groups such as amino, carboxy or hydroxy it may be desirable toprotect the group in some of the reactions mentioned herein.

A suitable protecting group for an amino or alkylamino group is, forexample, an acyl group, for example an alkanoyl group such as acetyl, analkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl ortert-butoxycarbonyl group, an arylmethoxycarbonyl group, for examplebenzyloxycarbonyl, or an aroyl group, for example benzoyl. Thedeprotection conditions for the above protecting groups necessarily varywith the choice of protecting group. Thus, for example, an acyl groupsuch as an alkanoyl or alkoxycarbonyl group or an aroyl group may beremoved for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a tert-butoxycarbonyl group may beremoved, for example, by treatment with a suitable acid as hydrochloric,sulphuric or phosphoric acid or trifluoroacetic acid and anarylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid for example borontris(trifluoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group which may beremoved by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoyl, or an arylmethyl group, for example benzyl. Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or an aroyl group may be removed, for example,by hydrolysis with a suitable base such as an alkali metal hydroxide,for example lithium or sodium hydroxide. Alternatively an arylmethylgroup such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a tert-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

The protecting groups may be removed at any convenient stage in thesynthesis using conventional techniques well known in the chemical art.

In order to use a compound of the Formula (I), or apharmaceutically-acceptable salt or in vivo cleavable ester thereof, forthe therapeutic treatment (including prophylactic treatment) of mammalsincluding humans, it is normally formulated in accordance with standardpharmaceutical practice as a pharmaceutical composition.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular orintramuscular dosing or as a suppository for rectal dosing).

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

Suitable pharmaceutically-acceptable excipients for a tablet formulationinclude, for example, inert diluents such as lactose, sodium carbonate,calcium phosphate or calcium carbonate, granulating and disintegratingagents such as corn starch or algenic acid; binding agents such asstarch; lubricating agents such as magnesium stearate, stearic acid ortalc; preservative agents such as ethyl or propyl p-hydroxybenzoate, andanti-oxidants, such as ascorbic acid. Tablet formulations may beuncoated or coated either to modify their disintegration and thesubsequent absorption of the active ingredient within thegastrointestinal tract, or to improve their stability and/or appearance,in either case, using conventional coating agents and procedures wellknown in the art.

Compositions for oral use may be in the form of hard gelatin capsules inwhich the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules in which the active ingredient is mixed with water oran oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finelypowdered form together with one or more suspending agents, such assodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone,gum tragacanth and gum acacia; dispersing or wetting agents such aslecithin or condensation products of an alkylene oxide with fatty acids(for example polyoxyethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives (such as ethyl orpropyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid),colouring agents, flavouring agents, and/or sweetening agents (such assucrose, saccharine or aspartame).

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil (such as arachis oil, olive oil, sesame oil orcoconut oil) or in a mineral oil (such as liquid paraffin). The oilysuspensions may also contain a thickening agent such as beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set outabove, and flavouring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water generally contain the activeingredient together with a dispersing or wetting agent, suspending agentand one or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients such as sweetening, flavouring and colouringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, or a mineral oil, such as for exampleliquid paraffin or a mixture of any of these. Suitable emulsifyingagents may be, for example, naturally-occurring gums such as gum acaciaor gum tragacanth, naturally-occurring phosphatides such as soya bean,lecithin, an esters or partial esters derived from fatty acids andhexitol anhydrides (for example sorbitan monooleate) and condensationproducts of the said partial esters with ethylene oxide such aspolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavouring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such asglycerol, propylene glycol, sorbitol, aspartame or sucrose, and may alsocontain a demulcent, preservative, flavouring and/or colouring agent.

The pharmaceutical compositions may also be in the form of a sterileinjectable aqueous or oily suspension, which may be formulated accordingto known procedures using one or more of the appropriate dispersing orwetting agents and suspending agents, which have been mentioned above. Asterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally-acceptable diluent or solvent,for example a solution in 1,3-butanediol.

Suppository formulations may be prepared by mixing the active ingredientwith a suitable non-irritating excipient which is solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum to release the drug. Suitable excipients include, forexample, cocoa butter and polyethylene glycols.

Topical formulations, such as creams, ointments, gels and aqueous oroily solutions or suspensions, may generally be obtained by formulatingan active ingredient with a conventional, topically acceptable, vehicleor diluent using conventional procedures well known in the art.

Compositions for administration by insufflation may be in the form of afinely divided powder containing particles of average diameter of, forexample, 30 μm or much less, the powder itself comprising either activeingredient alone or diluted with one or more physiologically acceptablecarriers such as lactose. The powder for insufflation is thenconveniently retained in a capsule containing, for example, 1 to 50 mgof active ingredient for use with a turbo-inhaler device, such as isused for insufflation of the known agent sodium cromoglycate.

Compositions for administration by inhalation may be in the form of aconventional pressurised aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient.

For further information on formulation the reader is referred to Chapter25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch;Chairman of Editorial Board), Pergamon Press 1990.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 2 g of active agent compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition. Dosage unit forms will generallycontain about 1 mg to about 500 mg of an active ingredient. For furtherinformation on Routes of Administration and Dosage Regimes the reader isreferred to Chapter 25.3 in Volume 5 of Comprehensive MedicinalChemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press1990.

The size of the dose for therapeutic or prophylactic purposes of acompound of the Formula (I) will naturally vary according to the natureand severity of the conditions, the age and sex of the animal or patientand the route of administration, according to well known principles ofmedicine.

In using a compound of the Formula (I) for therapeutic or prophylacticpurposes it will generally be administered so that a daily dose in therange of, for example, 0.5 mg to 75 mg per kg body weight is received,given if required in divided doses. In general lower doses will beadministered when a parenteral route is employed. Thus, for example, forintravenous administration, a dose in the range of, for example, 0.5 mgto 20 mg per kg body weight will generally be used. Intranvenousadministration is however preferred, typically, intravenous doses ofabout 10 mg to 500 mg per patient of a compound of this invention.

The vascular damaging treatment defined hereinbefore may be applied as asole therapy or may involve, in addition to the compound of theinvention, conventional surgery or radiotherapy or chemotherapy. Suchchemotherapy may include one or more of the following categories ofanti-tumour agents:

-   (i) antiproliferative/antineoplastic drugs and combinations thereof,    as used in medical oncology, such as alkylating agents (for example    cis-platin, carboplatin, cyclophosphamide, nitrogen mustard,    melphalan, chlorambucil, busulphan and nitrosoureas);    antimetabolites (for example antifolates such as fluoropyrimidines    like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine    arabinoside and hydroxyurea; antitumour antibiotics (for example    anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin,    epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin);    antimitotic agents (for example vinca alkaloids like vincristine,    vinblastine, vindesine and vinorelbine and taxoids like taxol and    taxotere); and topoisomerase inhibitors (for example    epipodophyllotoxins like etoposide and teniposide, amsacrine,    topotecan and camptothecin);-   (ii) cytostatic agents such as antioestrogens (for example    tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene),    antiandrogens (for example bicalutamide, flutamide, nilutamide and    cyproterone acetate), LHRH antagonists or LHRH agonists (for example    goserelin, leuprorelin and buserelin), progestogens (for example    megestrol acetate), aromatase inhibitors (for example as    anastrozole, letrozole, vorazole and exemestane) and inhibitors of    5α-reductase such as finasteride;-   (iii) Agents which inhibit cancer cell invasion (for example    metalloproteinase inhibitors like marimastat and inhibitors of    urokinase plasminogen activator receptor function);-   (iv) inhibitors of growth factor function, for example such    inhibitors include growth factor antibodies, growth factor receptor    antibodies (for example the anti-erbb2 antibody trastuzumab    [Herceptin™] and the anti-erbb1 antibody cetuximab [C225]), farnesyl    transferase inhibitors, tyrosine kinase inhibitors and    serine/threonine kinase inhibitors, for example inhibitors of the    epidermal growth factor family (for example EGFR family tyrosine    kinase inhibitors such as    N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine    (gefitinib, AZD 1839),    N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine    (erlotinib, OSI-774) and    6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine    (CI 1033)), for example inhibitors of the platelet-derived growth    factor family and for example inhibitors of the hepatocyte growth    factor family;-   (v) antiangiogenic agents such as those which inhibit the effects of    vascular endothelial growth factor, (for example the anti-vascular    endothelial cell growth factor antibody bevacizumab [Avastin™],    compounds such as those disclosed in International Patent    Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354)    and compounds that work by other mechanisms (for example linomide,    inhibitors of integrin α_(v)β3 function and angiostatin);-   (vi) vascular damaging agents such as Combretastatin A4 and    compounds disclosed in International Patent Applications WO    99/02166, WO00/40529, WO 00/41669, WO01/92224, WO02/04434 and    WO02/08213;-   (vii) antisense therapies, for example those which are directed to    the targets listed above, such as ISIS 2503, an anti-ras antisense;-   (viii) gene therapy approaches, including for example approaches to    replace aberrant genes such as aberrant p53 or aberrant BRCA1 or    BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such    as those using cytosine deaminase, thymidine kinase or a bacterial    nitroreductase enzyme and approaches to increase patient tolerance    to chemotherapy or radiotherapy such as multi-drug resistance gene    therapy; and-   (ix) immunotherapy approaches, including for example ex-vivo and    in-vivo approaches to increase the immunogenicity of patient tumour    cells, such as transfection with cytokines such as interleukin 2,    interleukin 4 or granulocyte-macrophage colony stimulating factor,    approaches to decrease T-cell anergy, approaches using transfected    immune cells such as cytokine-transfected dendritic cells,    approaches using cytokine-transfected tumour cell lines and    approaches using anti-idiotypic antibodies.

Such conjoint treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of thetreatment. Such combination products employ the compounds of thisinvention within the dosage range described hereinbefore and the otherpharmaceutically-active agent within its approved dosage range.

Examples of conditions wherein such combination therapy may beappropriate include: cancer, diabetes, psoriasis, rheumatoid arthritis,Kaposi's sarcoma, haemangioma, acute and chronic nephropathies,atheroma, arterial restenosis, autoimmune diseases, acute inflammation,endometriosis, dysfunctional uterine bleeding and ocular diseases withretinal vessel proliferation.

According to the seventh feature of the present invention there isprovided a compound of Formula (I), or salt, solvate or thereof,preferably in the form of a pharmaceutical composition, which when dosedin divided doses (also known as split doses) produces a greateranti-tumour effect than when a single dose is given.

Anti-tumour effects include but are not limited to, inhibition of tumourgrowth, tumour growth delay, regression of tumour, shrinkage of tumour,increased time to re-growth of tumour on cessation of treatment, slowingof disease progression. It is expected that when a compound of thepresent invention is administered to a warm-blooded animal such as ahuman, in need of treatment for cancer involving a solid tumour, saidmethod of treatment will produce an effect, as measured by, for example,one or more of: the extent of the anti-tumour effect, the response rate,the time to disease progression and the survival rate.

According to a further aspect of the seventh feature of the presentinvention there is provided a method for the production of a vasculardamaging effect in a warm-blooded animal such as a human, whichcomprises administering to said animal in divided doses an effectiveamount of a compound of Formula (I), or salt, or solvate thereof,preferably in the form of a pharmaceutical composition.

According to a further aspect of the seventh feature of the presentinvention there is provided a method for the treatment of a cancerinvolving a solid tumour in a warm-blooded animal such as a human, whichcomprises administering to said animal in divided doses an effectiveamount of a compound of Formula (I), or salt, or solvate thereof,preferably in the form of a pharmaceutical composition.

According to a further aspect of the seventh feature of the presentinvention there is provided a medicament comprising two or morefractions of doses of a compound of Formula (I), or salt, or solvatethereof, preferably in the form of a pharmaceutical composition, whichtogether add up to a total daily dose, for administration in divideddoses for use in a method of treatment of a human or animal body bytherapy.

According to a further aspect of the seventh feature of the presentinvention there is provided a kit comprising two or more fractions ofdoses of a compound of Formula (I), or salt, or solvate thereof,preferably in the form of a pharmaceutical composition, which togetheradd up to a total daily dose, for administration in divided doses.

According to a further aspect of the seventh feature of the presentinvention there is provided a kit comprising:

-   a) two or more fractions of doses of a compound of Formula (I), or    salt, or solvate thereof, which together add up to a total daily    dose, in unit dosage forms for administration in divided doses; and-   b) container means for containing said dosage forms.

According to a further aspect of the seventh feature of the presentinvention there is provided a kit comprising:

-   a) two or more fractions of doses of a compound of Formula (I), or    salt, or solvate thereof, which together add up to a total daily    dose, together with an excipient or carrier, in unit dosage forms;    and-   b) container means for containing said dosage forms.

According to a further aspect of the seventh feature of the presentinvention there is provided the use of a compound of Formula (I), orsalt, or solvate thereof, in the manufacture of a medicament foradministration in divided doses for use in the production of a vasculardamaging effect in a warm-blooded animal such as a human.

According to a further aspect of the seventh feature of the presentinvention there is provided the use of a compound of Formula (I), orsalt, or solvate thereof, in the manufacture of a medicament foradministration in divided doses for use in the production of ananti-cancer effect in a warm-blooded animal such as a human.

According to a further aspect of the seventh feature of the presentinvention there is provided the use of a compound of Formula (I), orsalt, or solvate thereof, in the manufacture of a medicament foradministration in divided doses for use in the production of ananti-tumour effect in a warm-blooded animal such as a human.

Divided doses, also called split doses, means that the total dose to beadministered to a warm-blooded animal, such as a human, in any one dayperiod (for example one 24 hour period from midnight to midnight) isdivided up into two or more fractions of the total dose and thesefractions are administered with a time period between each fraction ofabout greater than 0 hours to about 10 hours, preferably about 1 hour toabout 6 hours, more preferably about 2 hours to about 4 hours. Thefractions of total dose may be about equal or unequal.

Preferably the total dose is divided into two parts which may be aboutequal or unequal.

The time intervals between doses may be for example selected from: about1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours,about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about5.5 hours and about 6 hours.

The time intervals between doses may be any number (includingnon-integers) of minutes between greater than 0 minutes and 600 minutes,preferably between 45 and 375 minutes inclusive. If more than two dosesare administered the time intervals between each dose may be about equalor unequal.

Preferably two doses are given with a time interval in between them ofgreater than or equal to 1 hour and less than 6 hours.

More preferably two doses are given with a time interval in between themof greater than or equal to two hours and less than 5 hours.

Yet more preferably two doses are given with a time interval in betweenthem of greater than or equal to two hours and less than or equal to 4hours.

Particularly the total dose is divided into two parts which may be aboutequal or unequal with a time interval between doses of greater than orequal to about two hours and less than or equal to about 4 hours.

More particularly the total dose is divided into two parts which may beabout equal with a time interval between doses of greater than or equalto about two hours and less than or equal to about 4 hours.

For the avoidance of doubt the term ‘about’ in the description of timeperiods means the time given plus or minus 15 minutes, thus for exampleabout 1 hour means 45 to 75 minutes, about 1.5 hours means 75 to 105minutes. Elsewhere the term ‘about’ has its usual dictionary meaning.

Although the compounds of the Formula (I) are primarily of value astherapeutic agents for use in warm-blooded animals (including man), theyare also useful whenever it is required to inhibit and/or reverse and/oralleviate symptoms of angiogenesis and/or any disease state associatedwith angiogenesis. Thus, they are useful as pharmacological tools foruse in the development of new biological tests and in the search for newpharmacological agents.

Biological Assay

Colchicine Binding Site Competitive Assay Kit.

The ability of a ligand to bind specifically to the colchicine bindingsite on tubulin, an indicator of the vascular damaging activity, wasassessed using a size exclusion chromatography assay kit from“Cytoskeleton” (1650 Fillmore St. #240, Denver, Colo. 80206, U.S.A.)Catalogue number of kit: BK023.

The following reagents were used:

-   tubulin buffer, to give 0.1 mM GTP, 0.5 mM MgCl₂, 0.5 mM EGTA, 40 mM    PIPES buffer at pH 6.9 in the final reaction mix;-   purified tubulin protein from bovine brain at 1 mg/ml in tubulin    buffer;-   0.02 mM fluorescent colchicine in tubulin buffer [FITC (fluorescein    isothiocyanate)-labelled];-   2 mM colchicine in tubulin buffer;-   0.2 mM vinblastine in tubulin buffer; and-   G-25 Sephadex™ Fine-particle size 34–138 μm.

The reaction was performed as follows:

8 μl of test compound (dissolved in DMSO) was gently mixed with 150 μlof tubulin. This was then incubated at 37° C. for 30 minutes. Then 4 μlof the fluorescent colchicine was added, the incubation mix vortexed for5 seconds and then incubated for a further 30 minutes at 37° C.At the end of the reaction incubation size exclusion chromatography wasperformed to separate the tubulin with fluorescent colchicine bound fromthe free, unbound colchicine. If a test compound inhibited fluorescentcolchicine binding then a reduced signal is measured and the compound isconfirmed as a colchicine site binding moiety.

Chromatography was performed as follows, using chromatography columnsfilled with 3 mls of G-25 Sephadex™ Fine slurry. The incubation mixturewas pipetted onto the column and up to 12 elutions of 160 μl werecollected. The fluorescence of the tubulin-containing fractions wasdetected on a spectrophotometer which excites at 485 nm and emits at 535nm.

Control incubations were also performed, 8 μl DMSO (negative control)and 8 μl colchicine stock (positive competition control), instead of the8 μl of test compound in the incubation mixture.

The degree of competition of colchicine binding by either unlabelledcolchicine or test compound was calculated relative to the DMSO negativecontrol.

Compounds of Formula (I) encompass vascular damaging agents andpro-drugs of vascular damaging agents. Pro-drugs of vascular damagingagents are believed to be cleaved in-vivo. Without being bound bytheoretical considerations these pro-drugs may have lower activity inthe in-vitro colchicine binding site competitive assay, than would beanticipated when the activity of these compounds is measured in cellbased assays or in-vivo.

The invention will now be illustrated with the following non-limitingExamples in which, unless otherwise stated:

(i) evaporations were carried out by rotary evaporation in vacuo andwork-up procedures were carried out after removal of residual solidssuch as drying agents by filtration;

(ii) operations were carried out at ambient temperature, that is in therange 18–25° C. and under an atmosphere of an inert gas such as argon ornitrogen;

(iii) yields are given for illustration only and are not necessarily themaximum attainable;

(iv) the structures of the end-products of the Formula I were confirmedby nuclear (generally proton) magnetic resonance (NMR) and mass spectraltechniques; proton magnetic resonance chemical shift values weremeasured on the delta scale and peak multiplicities are shown asfollows: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad; q,quartet, quin, quintet;

(v) intermediates were not generally fully characterised and purity wasassessed by thin layer chromatography (TLC), high-performance liquidchromatography (HPLC), infra-red (IR) or NMR analysis;

(vi) flash chromatography was performed on silica (Merck Keiselgel: Art.9385);

(vii) OASIS™ is a macroporous co-polymer, used to purify hydrophiliccompounds, made from a balanced ratio of lipophillic divinylbenzene andhydrophillic N-vinylpyrrolidone. OASIS™ is described in the followingpatents, U.S. Pat. No. 5,882,521, U.S. Pat. No. 5,976,376 and U.S. Pat.No. 6,106,721. OASIS™ sample extraction products were obtained fromWaters Corporation (Milford, Mass., USA).

Abbreviations 4-Dimethylaminopyridine DMAP1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide EDCI hydrochlorideDi-isopropyl ethylamine DIEA Dimethyl sulphoxide DMSON-(9-fluorenylmethoxycarbonyl) N-FMOC N-methylpyrrolidine NMP

EXAMPLE 1 1-Methyl-2-carbamoyl-5-(3-aminobenzyloxy)-1H-indole

A suspension of 1-methyl-2-carbamoyl-5-(3-nitrobenzyloxy)-1H-indole(1.22 g; 3.75 mmol), Pt O₂ (0.18 g) and K₂CO₃ (0.18 g) in methanol (120ml) was hydrogenated under 45 psi for 1 hour.

The mixture was diluted with methanol, filtered on celite. Afterevaporation the residue was purified by flash chromatography elutingwith CH₂Cl₂/CH₃CN/MeOH 46/46/8 to give1-methyl-2-carbamoyl-5-(3-aminobenzyloxy)-1H-indole.

Yield: 70%

¹H NMR spectrum (DMSOd₆): 3.95 (s, 3H); 4.95 (s, 2H); 5.08 (bs, 2H);6.49 (ddd, 1H); 6.58 (d, 1H); 6.65 (dd, 1H); 6.94–7.04 (m, 31H); 7.13(d, 1H); 7.29 (bs, 1H); 7.42 (d, 1H); 7.88 (bs, 1H). MS-ESI: 296 [M+H]⁺

The starting material was prepared as follows:

1-Methyl-2-carbamoyl-5-hydroxy-1H-indole

A suspension of 1-methyl-2-carbamoyl-5-benzyloxy-1H-indole (1.94 g; 6.96mmol) and 10% Pd/C (0.5 g) in methanol (100 ml) was hydrogenated for 2hours. After filtration of the catalyst on celite, the filtrate wasevaporated to give 1-methyl-2-carbamoyl-5-hydroxy-1H-indole.

Yield: 95% ¹H NMR spectrum (DMSOd₆): 3.92 (s, 3H); 6.79 (dd, 1H); 6.88(d, 1H); 6.92 (s, 1H); 7.25 (bs, 1H); 7.31 (d, 1H); 7.83 (bs, 1H); 8.88(bs, 1H).

1-Methyl-2-carbamoyl-5-(3-nitrobenzyloxy)-1H-indole

A mixture of 1-methyl-2-carbamoyl-5-hydroxy-1H-indole (0.875 g; 4.6mmol), 2-nitrobenzyl bromide (1 g; 4.63 mmol) and Cs₂CO₃ (1.5 g; 4.63mmol) in acetonitrile (55 ml) was heated at 90° C. under argonatmosphere for 2 h 30. After evaporation to dryness, the residue wasextracted with CH₂Cl₂/H₂O. The organic phase was evaporated and theresidue triturated in CH₂Cl₂/ether to give1-methyl-2-carbamoyl-5-(3-nitrobenzyloxy)-1H-indole as a solid.

Yield: 86% ¹H NMR spectrum (DMSOd₆): 3.96 (s, 3H); 5.30 (s, 2H); 7.03(s, 1H); 7.05 (dd, 1H); 7.21 (d, 1H); 7.31 (bs, 1H); 7.46 (d, 1H); 7.71(dd, 1H); 7.90 (bs, 1H); 7.94 (d, 1H); 8.19 (dd, 1H); 8.33 (s, 1H).MS-ESI: 326 [M+H]⁺

EXAMPLE 2 2-Carbamoyl-5-(3-aminobenzyloxy)-1H-indole

2-Carbamoyl-5-(3-aminobenzyloxy)-1H-indole was prepared using the samegeneral method as described for Example 1.

Yield: 85% ¹H NMR spectrum (DMSOd₆): 4.95 (s, 2H); 5.09 (bs, 2H); 6.51(dd, 1H); 6.60 (d, 1H); 6.68 (s, 1H); 6.90 (dd, 1H); 6.99–7.05 (m, 2H);7.13 (d, 1H); 7.30 (bs, 1H); 7.32 (d, 1H); 7.90 (bs, 1H), 11.37 (s; 1H).MS-ESI: 280 [M−H]³¹

The starting material was prepared as follows:

2-Carbamoyl-5-hydroxy-1H-indole

2-Carbamoyl-5-benzyloxy-1H-indole (1 g; 3.35 mmol) in solution inmethanol (60 ml) was hydrogenated on 10% Pd/C (0.28 g) for 2 hours.After filtration on celite the solvent was evaporated to give2-carbamoyl-5-hydroxy-1H-indole which was used in the next step withoutfurther purification.

Yield: 100%

¹H NMR spectrum (DMSOd₆): 6.71 (dd, 1H); 6.86 (d, 2H); 7.20 (d, 1H);7.24 (bs, 1H); 7.81 (bs, 1H); 8.77 (bs, 1H); 11.20 (bs, 1H).

2-Carbamoyl-5-(3-nitrobenzyloxy)-1H-indole

This was prepared using the same general method as described in Example1.

Yield: 38% ¹H NMR spectrum (DMSOd₆): 5.27 (d, 2H); 6.96 (dd, 1H); 7.02(s, 1H); 7.19 (d, 1H); 7.30 (bs, 1H); 7.34 (d, 1H); 7.70 (dd, 1H); 7.90(bs, 1H); 7.94 (d, 1H); 8.19 (dd, 1H); 8.33 (s, 1H); 11.42 (bs, 1H).

EXAMPLE 3 2-Carbamoyl-5-[3-(α-glutamylamino)benzyloxy]-1H-indole

2-Carbamoyl-5-[3-(O-tert-butyl-α-glutamylamino)benzyloxy]-1H-indole(0.29 g; 0.62 mmol) in solution in CH₂Cl₂ (2 ml) was treated under argonwith HCl (2N) in dioxan (4 ml). The mixture was stirred for one hour,evaporated and the residue was purified on OASIS resin, eluting withH₂O/CH₃CN 80/20 to give2-carbamoyl-5-[3-(α-glutamylamino)benzyloxy]-1H-indole.

Yield: 51% ¹H NMR spectrum (DMSOd₆): 1.97–2.10 (m, 2H); 2.34–2.44 (m,2H)); 3.94 (t, 1H); 5.10 (s, 2H); 6.91 (dd, 1H); 7.01 (d, 1H); 7.16 (d,1H); 7.22 (d, 1H); 7.31 (bs, 1H); 7.32 (d, 1H); 7.37 (dd, 1H); 7.60 (d,1H); 7.73 (s, 1H); 7.90 (bs, 1H); 8.96 (bs, 2H); 10.63 (bs, 1H); 11.41(s, 1H).

Elemental analysis Found C 54.54 H 5.5 N 12.45 C₂₁H₂₂N₄O₅, 0.7 H₂O, 1HCl Requires C 54.89 H 5.35 N 12.19

The starting material was prepared as follows:

2-Carbamoyl-5-[3-(tert-butyl-α-glutamylamino)benzyloxy]-1H-indole

A solution of 2-carbamoyl-5-(3-aminobenzyloxy)-1H-indole (Example 2)(0.28 g; 1 mmol) in CH₃CN (10 ml) was added to a solution of DIEA (0.191ml; 1.1 mmol), HATU (0.418 g; 1.1 mmol) and 10 (0.467 g; 1.1 mmol) inCH₂Cl₂ (7 ml). The mixture was stirred overnight under argon atmosphere.After evaporation, the residue was purified by flash chromatographyeluting with CH₂Cl₁ and CH₂Cl₂/Acetone 60/40 to give 9.

A solution of 9 (0.51 g; 0.74 mmol) and piperidine (0.8 ml) in CH₂Cl₂(10 ml) was stirred at ambient temperature for 3 hours. Afterevaporation to dryness, the residue was purified by flash chromatographyeluting with CH₂Cl₂, CH₂Cl₂/CH₃CN 90/10 and then with CH₂Cl₂/CH₃CN/MeOH45/45/10 to give2-carbamoyl-5-[3-(tert-butyl-α-glutamylamino)benzyloxy]-1H-indole.

Yield: 87% ¹H NMR spectrum (DMSOd₆): 1.38 (s, 9H); 1.59–1.76 (m, 1H);1.81–1.93 (m, 1H); 2.22–2.36 (m, 2H); 3.27–3.34 (m, 2H); 5.07 (s, 2H);6.10 (dd, 1H); 7.01 (d, 1H); 7.12–7.18 (m, 2H); 7.26–7.35 (m, 3H); 7.59(d, 1H); 7.77 (s, 1H); 7.88 (bs, 1H); 9.8 (bs, 2H); 11.38 (s, 1H).

EXAMPLE 41-Methyl-2-carbamoyl-5-[3-(α-glutamylamino)benzyloxy]-1H-indole

1-Methyl-2-carbamoyl-5-[3-(α-glutamylamino)benzyloxy]-1H-indole wasprepared using the same general method as described for Example 3.

Yield: 81% ¹H NMR spectrum (DMSOd₆): 2.02–2.12 (m, 2H); 2.36–2.44 (m,2H); 3.97 (s, 3H); 4.01 (t, 1H); 5.12 (s, 2H); 7.00 (dd, 1H); 7.03 (s,1H); 7.17 (d, 1H); 7.23 (d, 1H); 7.31 (bs, 1H); 7.38 (dd, 1H); 7.44 (d,1H); 7.60 (d, 1H); 7.23 (s, 1H); 7.90 (bs, 1H); 8.83 (bs, 2H); 10.72 (s,1H). MS-ESI: 423 [M−H]³¹

Elemental analysis Found C 55.04 H 5.53 N 11.49 C₂₂H₂₄N₄O₅, 0.9 H₂O, 1HCl Requires C 55.38 H 5.66 N 11.74

The starting material was prepared using analogous methodology to thatdescribed in Example 3 for the synthesis of2-carbamoyl-5-[3-(tert-butyl-α-glutamylamino)benzyloxy]-1H-indole.

1-Methyl-2-carbamoyl-5-[3-(tert-butyl-α-glutamylamino)benzyloxy]-1H-indole

Yield: 75% (for the 2 steps) ¹H NMR spectrum (DMSOd6): 1.38 (s, 9H);1.64–1.73 (m, 1H); 1.83–1.93 (m, 1H); 2.22–2.40 (m, 2H); 3.34–3.38 (m,1H); 3.96 (s, 3H); 5.09 (s, 2H); 6.94-dd, 1H); 7.02 (s, 1H); 7.12–7.20(m, 2H); 7.25–7.36 (m, 2H); 7.43 (d, 1H); 7.59 (d, 1H); 7.76 (s, 1H);7.89 (bs, 1H); 10.0 (bs, 1H), 11.39 (s,1H). MS-ESI: 481 [M+H]⁺

EXAMPLE 5 3-Carbamoylmethyl-5-(3-aminobenzyloxy)-1H-indole

3-Carbamoylmethyl-5-(3-aminobenzyloxy)-1H-indole was prepared using thesame general method as described for Example 1.

Yield: 69% ¹H NMR spectrum (DMSOd₆): 3.43 (s, 2H)); 4.91 (s, 2H); 5.09(bs, 2H); 6.51 (dd, 1H); 6.60 (d, 1H); 6.70 (s, 1H); 6.78 (dd, 1H); 6.82(bs, 1H); 7.02 (dd, 1H); 7.17 (s,1H); 7.16 (d, 1H); 7.24 (d, 1H); 7.29(bs, 1H); 10.71 (s, 1H). MS-ESI: 296 [M+H]⁺

The starting material was prepared using analogous methodology to thatdescribed in Example 1 for intermediate 1.

3-Carbamoylmethyl-5-(3-nitrobenzyloxy)-1H-indole

Yield: 58% ¹H NMR spectrum (DMSOd₆): 3.44 (s, 2H); 5.26 (d, 2H); 6.82(bs, 1H); 6.87 (dd, 1H); 7.18 (d,1H); 7.20 (dd, 1H); 7.28 (bs, 1H); 7.28(d, 1H); 7.72 (dd, 1H); 7.97 (d, 1H); 8.21 (dd, 1H); 8.36 (s, 1H); 10.77(s, 1H). MS-ESI: 326 [M+H]⁺

EXAMPLE 6 3-Carbamoylmethyl-5-(3-α-glutamylbenzyloxy)-1H-indole

3-Carbamoylmethyl-5-(3-α-glutamylbenzyloxy)-1H-indole was prepared usingthe same general method as described in Example 3 by deprotection of 15.

Yield: 27% ¹H NMR spectrum (DMSOd₆): 2.01–2.14 (m, 2H); 2.36–2.44 (m,2H); 3.42 (s, 2H); 3.98–4.08 (m, 1H); 5.08 (s, 2H); 6.77–6.83 (m, 2H);7.16 (dd, 1H); 7.18 (d, 1H); 7.21–7.27 (m, 2H); 7.30 (bs, 1H); 7.38 (dd,1H); 7.61 (d, 1H); 7.74 (s, 1H); 8.37 (bs, 2H); 10.74 (s, 1H); 12.38(bs, 1H). MS-ESI: 425 [M+H]⁺

The starting material 15 was prepared using analogous method to thatdescribed in Example 3 starting from3-carbamoylmethyl-5-(3-aminobenzyloxy)-1H-indole (Example 5).

Yield: 45.9% ¹H NMR spectrum (DMSOd₆) 1.26 (s, 3H); 1.30 (s, 3H); 1.42(s, 9H); 1.65–1.78 (m, 1H); 1.93–2.05 (m, 1H); 2.30–2.45 (m, 2H); 3.41(s, 2H); 3.54–3.62 (m, 1H); 5.10 (m, 2H); 6.79 (bs, 1H); 6.81 (dd, 1H);7.10–7.31 (m, 6H); 7.46–7.49 (m, 2H)); 10.71 (s, 1H).

EXAMPLE 7 2-Carbamoyl-6-benzyloxy-1H-indole

A solution of 2-carboxy-6-benzyloxy-1H-indole (0.125 g; 0.468 mmol),oxalyl chloride (0.5 mmol) and DMF (0.2 ml) in CH₂Cl₂ was stirred atroom temperature for 2 hours. After evaporation to dryness, the residuewas redissolved in acetone; ammonium acetate (0.074 g; 0.95 mmol) wasadded to the solution and the mixture was stirred at room temperaturefor 1 hour. After evaporation, the residue was purified by flashchromatography eluting with CH₂Cl₂/acetone 80/20 to give2-carbamoyl-6-benzyloxy-1H-indole.

Yield: 70% ¹H NMR spectrum (DMSOd₆): 5.10 (s, 2H); 6.77 (dd, 1H); 6.96(d, 1H); 7.04 (d, 1H); 7.21 (bs, 1H); 7.33 (t, 1H); 7.40 (t, 2H);7.46–7.50 (m, 3H); 7.82 (bs, 1H); 11.34 (s, 1H). MS-ESI: 265 [M−H]⁻

EXAMPLE 8 2-Acetyl-5-phenoxy-1H-indole

EtI (0.23 ml; 2.87 mmol) was added under argon atmosphere to asuspension of Mg (0.07 g; 2.87 mmol) in ether (3 ml). After stirring for20 minutes, 19 (0.3 g; 1.43 mmol) in solution in ether (7 ml) was added.The mixture was stirred for 1 hour, cooled to 10° C. and acetyl chloride(0.113 ml; 1.58 mmol) was added. After stirring at 10° C. for 30minutes, the mixture was poured in ether/H₂O. The organic phase wasevaporated and purified by flash chromatography eluting with petroleumether/AcOEt 60/40 to give 2-acetyl-5-phenoxy-1H-indole.

Yield: 30% ¹H NMR spectrum (DMSOd₆): 2.41 (s, 3H); 6.94 (d, 2H); 6.97(dd, 1H); 7.07 (t, 1H); 7.35 (dd, 2H); 7.49 (d, 2H); 7.75 (d, 1H); 8.34(d, 1H); 11.99 (bs, 1H). MS-ESI: 250 [M−H]⁻

EXAMPLE 9 3-Methoxycarbonyl-5-phenylsulphanyl-1H-indole

Mg (0.073 g; 3 mmol) was added under argon atmosphere to a solution ofEtI (0.240 ml; 3 mmol) in ether (4 ml). After stirring for 20 minutes,20 (0.338 g; 1.5 mmol) in solution in ether (5 ml) was added. Themixture was cooled to 10° C. and methyl chloroformate (0.128 ml; 1.65mmol) was added. After stirring for 15 minutes, the mixture wasextracted with AcOEt/H₂O. The organic phase was evaporated to give3-methoxycarbonyl-5-phenylsulphanyl-1H-indole after purification byflash chromatography and elution with petroleum ether/AcOEt 95/5.

Yield: 28% ¹H NMR spectrum (DMSOd₆): 3.80 (s, 3H); 7.12–7.21 (m, 3H);7.26–7.32 (m, 3H); 7.56 (d, 1H); 8.13–8.18 (m, 1H); 12.15 (bs, 1H).MS-ESI: 282 [M−H]⁻

EXAMPLE 10 3-Cyano-5-phenylsulphanyl-1H-indole

To a stirred solution of 20 (0.45 g; 2 mmol) in CH₃CN (6 ml) at 0° C.was added chlorosulfonyl isocyanate (0.175 ml; 2 mmol) in solution inCH₃CN (6 ml). Et₃N (0.272 ml; 1.96 mmol) was added over 45 minutes,maintaining the temperature near 0° C. The resulting solution wasstirred at room temperature for 2 hours. The solvent was removed and theresidue extracted with CH₂Cl₂/sat. aq. NaHCO₃. The organic phase waspurified by flash chromatography eluting with CH₂Cl₂/EtOH 98/2 to giveafter trituration in ether 3-cyano-5-phenylsulphanyl-1H-indole as asolid.

Yield: 38% ¹H NMR spectrum (CDCl₃): 7.16–7.23 (m, 1H); 7.25–7.29 (m,4H); 7.38–7.46 (m, 2H); 7.75 (d, 1H); 7.90 (s, 1H); 8.75 (bs, 1H).

EXAMPLE 11 3-Cyano-5-phenoxy-1H-indole

3-Cyano-5-phenoxy-1H-indole was prepared using the same method asdescribed for Example 10 but starting from 21.

Yield: 62% ¹H NMR spectrum (DMSOd₆): 6.99 (d, 2H); 7.04 (d, 1H); 7.12(t, 1H); 7.16 (d, 1H) 7.38 (dd, 2H); 7.58 (d, 1H); 8.27 (s, 1H); 12.22(bs, 1H). MS-ESI: 233 [M−H]⁻

EXAMPLE 12 3-Carbamoyl-5-phenoxy-1H-indole

To a solution of 3-Cyano-5-phenoxy-1H-indole (Example 11) (0.105 g; 0.45mmol) in EtOH (3 ml) and 1N NaOH (1.5 ml) was added H₂O₂ (0.15 ml). Themixture was heated at 50° C. for 1 h 30 mn, diluted with water, cooledto 5° C. and neutralised to pH 7 with 1N HCl.

The mixture was extracted with AcOEt, evaporated to dryness and purifiedby flash chromatography, eluting with petroleum ether/AcOEt 50/50 togive 3-carbamoyl-5-phenoxy-1H-indole.

Yield: 35% ¹H NMR spectrum (DMSOd₆): 6.77 (bs, 1H); 6.89–6.96 (m, 3H);7.05 (dd, 1H); 7.34 (dd, 2H); 7.40 (bs, 1H); 7.45 (d, 1H); 7.76 (d, 1H);8.06 (d, 1H); 11.59 (bs, 1H). MS-ESI: 253 [M−H]⁻

EXAMPLE 13 3-Carbamoyl-5-(4-hydroxyphenoxy)-1H-indole

To a stirred solution of 22 (0.25 g; 0.79 mmol) in ether (10 ml) at 0°C. was added chlorosulphonyl isocyanate (0.561 g; 3.9 mmol). Thesolution was stirred for 20 minutes. The precipitate was collected byfiltration, redissolved in THF (3 ml) and exposed to light for 30minutes. After evaporation, the residue was taken up in methanol (5 ml).Ammonium acetate (0.498 g; 0.79 mmol) and Pd/C (0.05 g) were added. Thesuspension was heated to 80° C. for 30 minutes. After filtration andtrituration with water, the solid was washed with ether to give3-carbamoyl-5-(4-hydroxyphenoxy)-1H-indole.

Yield: 52% ¹H NMR (DMSOd₆): 6.84 (m, 5H); 7.42 (dd, 1H); 7.65 (m, 1H);8.08 (s, 1H). MS-ESI: 267 [M−H]⁻

The starting material was prepared as follows:

2-Methyl-4-(4-benzyloxyphenoxy)-nitrobenzene

To a stirred slurry of 23 (25 g; 124.9 mmol) and K₂CO₃ (34.5 g; 249.8mmol) in NMP (100 ml) was added 5-fluoro-2-nitrotoluene (19.56 g; 126.1mmol). The mixture was heated to 180° C. for 2 hours. The suspension wascooled to room temperature and the product was precipitated into water(300 ml). The solid was filtered and purified by flash chromatographyeluting with heptane/CH₂Cl₂ 50/50 to give2-methyl-4-(4-benzyloxyphenoxy)-nitrobenzene (25).

Yield: 93% ¹H NMR (DMSOd₆): 3.32 (s, 3H); 5.11 (s, 2H); 6.86 (m, 1H);6.99 (m, 1H); 7.11 (m, 5H); 7.3–7.5 (m, 5H).

3-Carbamoyl-5-(4-benzyloxyphenoxy)-1H-indole

To a stirred solution of 25 (40 g; 119.4 mmol) and pyrrolidine (8.49 g;119.4 mmol) in dry DMF (40 ml) was added N,N-dimethyl formamide dimethylacetal (42.7 g; 3.58 mmol). The mixture was heated to 120° C. for 2hours and extracted with ether/H₂O. The organic phase was evaporated togive a red solid. 40 g of the solid in solution in toluene-acetic acid(500 ml; 3:2) were added to a stirred suspension of Fe (80 g; 1.43 mol)and silica gel (130 g) in a mixture of toluene-acetic acid (1.5 1; 3:2).The reaction mixture was heated to 100° C. for 1 hour. The suspensionwas cooled to ambient temperature and filtered through celite. Thefiltrate was concentrated to afford an oil which was purified by flashchromatography, eluting with heptane/CH₂Cl₂ 50/50 to give 22.

Yield: 43% ¹H NMR (DMSOd₆): 5.05 (s, 2H); 6.36 (m, 1H); 6.80 (dd, 1H);6.89 (d, 2H); 6.97 (d, 2H); 7.09 (m, 1H); 7.39 (m, 7H). MS-ESI: 316[M+H]⁺

EXAMPLE 14 3-Carbamoyl-5-(4-phosphonoxyphenoxy)-1H-indole

To a mixture of1-tert-butyloxycarbonyl-3-carbamoyl-5-(4-phosphonoxyphenoxy)-1H-indole(26) (0.47 g; 1 mmol) in CH₂Cl₂ was added TFA (25 ml). The solution wasstirred for 2 hours. The solvent was evaporated and the solid purifiedon Oasis resin eluting with a 0–30% gradient MeOH/H₂O. After evaporationof methanol, the pH was adjusted to 7.5 with 0.1N NaOH to give afterfreeze drying 3-carbamoyl-5-(4-phosphonoxyphenoxy)-1H-indole.

Yield: 80% ¹H NMR (DMSOd₆): 6.83 (m, 3H); 7.16 (d, 2H); 7.45 (d, 1H);7.75 (s, 1H); 8.09 (s, 1H). MS-ESI: 349 [M+H]⁻⁺

The starting material was prepared as follows:

3-Carbamoyl-5-(4-benzyloxyphenoxy)-1H-indole

To a stirred solution of 23 (2 g; 6.3 mmol) in ether (100 ml) at 0° C.was added chlorosulphonyl isocyanate (4.49 g; 32 mmol). The solution wasstirred at 0° C. for 1 hour. The solid was collected by filtration anddissolved in THF (20 ml). The solution was exposed to light for 1 hour.After evaporation the residue was purified by flash chromatographyeluting with CH₂Cl₂/MeOH 85/15 to give 27.

Yield: 94% ¹H NMR (DMSO): 5.08 (s, 2H); 6.88 (m, 3H); 7.04 (d, 12H);7.41 (m, 5H); 7.67 (m, 1H); 8.05 (m, 1H). MS-ESI: 359 [M+H]⁺

1-tert-Butyloxycarbonyl-3-carbamoyl-5-(4-benzyloxyphenoxy)-1H-indole

To a stirred solution of 27 (2 g; 5.6 mmol) in acetonitrile (100 ml)were added DMAP (0.034 g; 0.28 mmol) and di-tert-butyldicarbonate (1.22g; 5.6 mmol). The suspension was stirred for 1 hour. The solvent wasevaporated and the residue taken up in AcOEt (100 ml), washed with 10%citric acid and purified by flash chromatography eluting withCH₂Cl₂/MeOH 95/5 to give 28.

Yield: 61% ¹H NMR (DMSO): 1.66 (s, 9H); 5.09 (s, 2H); 7.05 (m, 5H); 7.14(brs, 1H); 7.41 (m, 3H); 7.47 (d, 2H); 7.75 (m, 1H); 7.86 (brs, 1H);8.05 (d, 1H); 8.48 (s, 1H). MS-ESI: 459 [M+H]⁺

1-tert-Butyloxycarbonyl-3-carbamoyl-5-(4-hydroxyphenoxy)-1H-indole

To a solution of 28 (1.39 g; 2.8 mmol) in AcOEt/EtOH (1:2; 150 ml), 10%Pd/C (0.6 g) was added and the suspension was hydrogenated for 2 hours.After filtration on celite the filtrate was evaporated to dryness togive 29.

Yield: 98% ¹H NMR (DMSO): 1.64 (s, 9H); 6.78 (2H, d); 6.88 (d, 2H); 7.05(dd, 1H); 7.11 (brs, 1H); 7.69 (m, 1H); 7.80 (brs, 1H); 7.99 (dd, 1H);8.45 (s, 1H); 9.30 (brs, 1H). MS-ESI: 367 [M+H]⁺

1-tert-Butyloxycarbonyl-3-carbamoyl-5-[4-(di-benzyloxy-phosphonoxy)phenoxy]-1H-indole

To a stirred solution of 29 (1.03 g; 2.8 mmol), CCl₄ (4.31 g; 28 mmol),DIPEA (1.81 g; 14 mmol) and DMAP (0.02 g) in acetonitrile (10 ml) at 0°C. was added dibenzyl phosphite (4.41 g; 16.8 mmol) over a period of 30minutes. The mixture was allowed to warm to room temperature and stirredfor 1 hour. After evaporation, the residue was taken up in CH₂Cl₂ (200ml), washed with 10% citric acid. The organic layer was evaporated andpurified by flash chromatography eluting with CH₂Cl₂/AcOEt 50/50 to give30.

Yield: 63% ¹H NMR (DMSOd₆): 1.67 (s, 9H); 5.19 (s, 4H)); 7.00 (d, 2H);7.12 (dd, 1H); 7.20 (d, 2H); 7.39 (9H, m); 7.85 (d, 1H); 8.10 (d, 2H);8.52 (s, 1H). MS-ESI: 629 [M+H]⁺

1-tert-Butyloxycarbonyl-3-carbamoyl-5-(4-phosphonoxyphenoxy)-1H-indole

To a stirred solution of 30 (1.1 g; 1.8 mmol) in AcOEt/EtOH (30 ml; 1:1)was added 10% Pd/C (0.2 g). The suspension was hydrogenated for 1 hour.After filtration of the catalyst the solvent was evaporated to give 26as a foam.

Yield: 58% ¹H NMR (DMSOd₆): 1.65 (s, 9H); 6.99 (d, 2H); 7.10 (dd, 1H);7.14 (d, 2H); 7.91 (m, 1H); 7.97 (brs, 1H); 8.07 (d, 1H); 8.49 (s, 1H).

MS-ESI: 449 [M+H]⁺

EXAMPLE 15 3-Cyano-5-(4-hydroxyphenoxy)-1H-indole

To a stirred solution of 31 (0.2 g; 0.6 mmol) in AcOEt/EtOH (1:1; 100ml) was added 10% Pd/C (0.05 g). The suspension was hydrogenated for 1hour. After filtration and evaporation, the residue was purified byflash chromatography eluting with CH₂Cl₂/MeOH 95/5 to give3-cyano-5-(4-hydroxyphenoxy)-1H-indole.

Yield: 100% ¹H NMR (DMSOd₆): 6.78 (m, 3H); 6.89 (d, 2H); 6.96 (m, 2H);7.53 (dd, 1H); 8.22 (s, 1H). MS-ESI: 249 [M+H]⁺

The starting material was prepared as follows:

3-Cyano-5-(4-benzyloxyphenoxy)-1H-indole

To a stirred suspension of 22 (0.36 g; 1.14 mmol) in ether (20 ml) wasadded chlorosulphonyisocyanate (0.80 g; 5.7 mmol) at 0° C. The mixturewas stirred for 1 hour at 0° C. The resulting solid was collected byfiltration, redissolved in THF (20 ml) and exposed to light for 1 hour.After evaporation, the residue was purified by flash chromatographyeluting with CH₂Cl₂ to give 31 as the by product.

Yield: 17% ¹H NMR (DMSO) 5.06 (s, 2H); 6.92 (m, 3H); 6.98 (d, 2H); 7.39(m, 6H); 7.68 (m, 1H); 8.04 (m, 1H). MS-ESI: 339.53 [M+H]⁺

EXAMPLE 16 1-Methyl-3-carbamoyl-5-(4-hydroxyphenoxy)-1H-indole

To a stirred solution of 32 (0.2 g; 0.5 mmol) in EtOH (50 ml) was addedPd(OH)₂ (0.05 g). The suspension was hydrogenated for 1 hour. Afterfiltration and evaporation, the residue was purified by flashchromatography eluting with CH₂Cl₂/MeOH to give1-methyl-3-carbamoyl-5-(4-hydroxyphenoxy)-1H-indole.

Yield: 53% ¹H NMR (DMSO): 3.82 (s, 3H); 6.74 (d, 2H); 6.82 (d, 2H); 6.91(dd, 1H); 7.48 (dd, 1H); 7.66 (dd, 1H); 7.98 (s, 1H); 9.21 (s, 1H).MS-ESI: 281 [M−H]⁻

The starting material was prepared as follows

1-Methyl-3-carbamoyl-5-(4-benzyloxyphenoxy)-1H-indole

To a stirred solution of 27 (0.26 g; 0.76 mmol) in THF (3 ml), at 0° C.was added NaH (0.032 g; 0.8 mmol). MeI (0.108 g; 0.76 mmol) was added.The reaction was stirred at room temperature for 1 hour. Afterevaporation the residue was purified by flash chromatography, elutingwith CH₂Cl₂/MeOH 90/10 to give 32.

Yield: 70% ¹H NMR (DMSO): 3.81 (s, 3H); 5.07 (s, 2H); 6.91 (m, 3H); 6.99(d, 2H); 7.39 (m, 6H); 7.68 (m, 1H); 7.98 (s, 1H). MS-ESI: 373 [M+H]⁺

EXAMPLE 17 2-Cyano-5-benzyloxy-1H-indole

Trichloromethylchloroformate (0.087 ml; 0.72 mmol) was added to 33 (0.12g; 0.451 mmol) and trimethyl phosphite (0.21 ml). The mixture was heatedat 60° C. for 5 minutes, diluted with water and extracted with ether.The organic phase was evaporated, the residue was purified by flashchromatography, eluting with CH₂Cl₂ to give2-cyano-5-benzyloxy-1H-indole.

Yield: 62% ¹H NMR spectrum (DMSOd₆): 5.11 (s, 2H); 7.07 (dd, 1H); 7.21(d, 1H); 7.23 (d, 1H); 7.33 (dd, 1H); 7.36–7.43 (m, 3H); 7.47 (d, 2H);12.25 (bs, 1H). MS-ESI: 247 [M−H]⁻

EXAMPLE 18 1-Methyl-3-cyano-5-(4-hydroxy-3,5-dimethoxyphenoxy)-1H-indole

To a solution of 1-methyl-3-cyano-5-(3,4,5-trimethoxyphenoxy)-1H-indole(500 mg; 1.47 mmol) in CH₂Cl₂ (10 ml) was added trimethylsilyl iodide(831 μl; 5.84 mmol). After stirring at room temperature under argonatmosphere for 2 h30, the mixture was poured into cold water, extractedwith ethyl acetate. The organic phase was evaporated and the residue waspurified by flash chromatography on silica gel, eluting withCH₂Cl_(2/)Et₂O 1:1 to give1-methyl-3-cyano-5-(4-hydroxy-3,5-dimethoxyphenoxy)-1H-indole: (244 mg)

Elemental analysis Found C 66.19 H 4.98 N 8.47 C₁₈H₁₆N₂O₄ Requires C66.66 H 4.97 N 6.64

The starting material was prepared as follows:

2-Methyl-4-(3,4,5-trimethoxyphenoxy)-nitrobenzene

A solution of 35 (6 g; 32.5 mmol), 36 (5.0 g; 32.5 mmol) and K₂CO₃ (6.7g; 48.5 mmol) in NMP (65 ml) was heated at 80° C. under argon atmospherefor 3 h. After cooling, the mixture was poured on cold water and theprecipitate was filtrated, washed with water then pentane, and purifiedby flash chromatography, eluting with CH₂Cl₂ to give 37 as a yellowsolid: 9.3 g

Yield: 90%. ¹H NMR spectrum (DMSOd6): 2.55 (s, 3H); 3.68 (s, 3H); 3.72(s, 6H); 6.53 (s, 2H); 6.95 (dd, 1H); 7.07 (d, 1H); 8.07 (d, 1H).

To a solution of 37 (9.3 g; 29.15 mmol) in DMF (15 ml) was addedN,N-Dimethylformamide dimethyl acetal (4.5 ml; 33.8 ml) and pyrrolidine(2.8 ml; 33.8 mmol). The solution was heated at reflux (110° C.) underargon atmosphere for 2 h30. After evaporation under vacuum, the residuewas dissolved in CH₂Cl₂ (8 ml) and Methanol (6.4 ml). The solution wasconcentrated to about 6 ml and cooled to 5° C. The resulting solid wasfiltered and washed with cold methanol to give 34 as red crystals: 10.9g

Yield: 94% ¹H NMR spectrum (DMSOd₆): 1.89 (m, 4H); 3.30 (m, 4H); 3.67(s, 3H); 3.72 (s, 6H); 5.80 (d, 1H); 6.43 (d, 1H); 6,47 (s, 2H); 7.27(d, 1H); 7.64 (d, 1H); 7.88 (d, 1H).

5-(3,4,5-Trimethoxyphenoxy)-1H-indole

To a stirred solution of 34 (10.9 g; 27.25 mmol) in THF (48 ml) and MeOH(48 ml) at 30° C. under argon was added excess Raney nickel followed byhydrazine hydrate 85% (2.9 ml). Vigorous gas evolution was observed andtemperature rose to 46° C. An additional 2.9 ml of hydrazine hydrate wasadded 1 hr later. The temperature was maintained between 45–50° C. for 2h after the last addition. The catalyst was removed by filtration oncelite and was washed several times with CH₂Cl₂; after evaporation ofthe filtrate, the residue was purified by flash chromatography, elutingwith AcOEt/Essence G 4:6 then 1:1 to give 38 as a white solid: 3.5 g

Yield: 43%. ¹H NMR spectrum (DMSOd₆): 3.63 (s,3H); 3.68 (s,6H); 6.26 (s,2H); 6.41 (d, 1H); 6.83 (dd, 1H); 7.19 (d, 1H); 7.36 (m, 2H); 11.12 (s,1H).

3-Cyano-5-(3,4,5-trimethoxyphenoxy)-1H-indole

38 (2.3 g; 7.69 mmol) in solution in CH₃CN (7 ml) and Et₂O (10 ml) wastreated with Chlorosulfonyl isocyanate (1.33 ml; 15.38 mmol). Afterstirring for 1 hour, the solvents were removed and the residue wastriturated several times in pentane, dried under vacuum and then takenup in DMF (30 ml); the solution was stirred at room temperature for 1 hrand poured in cold water. The resulting precipitate was filtrated, driedand purified by flash chromatography on silica gel, eluting withCH₂Cl₂/Et₂O 1:1 to give 39 as a white solid: 2.02 g

Yield: 81%. ¹H NMR spectrum (DMSOd₆): 3.65 (s,3H); 3.71 (s,6H); 6.35 (s,2H); 7.02 (dd, 1H); 7.18 (d, 1H); 7.56 (d, 1H); 8.26 (s, 1H).

1-Methyl-3-cyano-5-(3,4,5-trimethoxyphenoxy)-1H-indole

39 (230 mg; 0.71 mmol) in solution in DMF (0.9 ml) was treated with NaH60% dispersed in mineral oil (33 mg; 0.71 mmol). The mixture was stirredunder argon atmosphere for 10 mn and CH₃I (73 μl; 0.78 mmol) was added.The mixture was stirred under argon atmosphere for 1 h and poured intocold water. The resulting white solid was filtrated washed with waterand dried under vacuum for a night to give 40:230 mg.

Yield: 96% ¹H NMR spectrum (DMSOd₆): 3.66 (s, 3H); 3.71 (s, 6H); 3.89(s, 3H); 6.35 (s, 2H); 7.10 (dd, 1H); 7.19 (d, 1H); 7.68 (d, 1H); 8.26(s, 1H).

EXAMPLE 191-Methyl-3-cyano-5-(4-phosphonoxy-3,5-dimethoxyphenoxy)-1H-indole

41 (470 mg; 0.91 mmol) in solution in CH₂Cl₂ (1 ml) was treated underargon with a 2N HCl in dioxan (6.5 ml). The mixture was stirred at roomtemperature for 2 hr, evaporated and the residue was purified bycrystallisation in Et₂O/pentane: 250 mg

Yield: 68%

Elemental analysis Found C 51.00 H 4.45 N 6.50 C₁₈H₁₇N₂O₇P, H₂O RequiresC 51.19 H 4.53 N 6.63

The starting material 41 was prepared as follows:

1-Methyl-3-cyano-5-[4-(di-tert-butylphosphonoxy)-3,5-dimethoxyphenoxy]-1H-indole

To a solution of M584994 (870 mg; 2.68 mmol) in THF (4 ml) was addedtetrazole (376 mg; 5.37 mmol) anddi-tert-butyl-N,N-diethylphosphoramidate (900 μl; 3.22 mmol). Themixture was stirred at room temperature for 2 hr, cooled to −40° C. anda solution of MCPBA (659 mg; 2.95 mmol) in CH₂Cl₂ (5 ml) was added.After stirring at 0° C. for 1 h, the mixture was poured on cold water,washed with NaHSO₃ and extracted with CH₂Cl₂. The organic phase waswashed with cold 2N NaOH and evaporated. The residue was purified byflash chromatography on silica gel, eluting with CH₂Cl₂/AcOEt 8:2 thenwith CH₂Cl₂/AcOEt/Acetone 8:1.5:0.5 to give 5:471 mg

Yield: 33.6% ¹H NMR spectrum (DMSOd₆): 1.45 (s, 18H); 3.70 (s, 6H); 3.89(s, 3H); 6.39 (s, 2H); 7.11 (dd, 1H); 7.18 (s, 1H); 7.70 (d, 1H); 8.27(s, 1H)

EXAMPLE 20 2-Carbamoyl-5-(2,5-dimethoxybenzyloxy)-1H-indole

A mixture of 42 (0.265 g; 1.5 mmol), 43 (0.381 g; 1.65 mmol) and Cs₂CO₃(0.536 g; 1.65 mmol) in acetonitrile (20 ml) was heated at 90° C. underargon atmosphere for 2 hours. After evaporation to dryness the residuewas purified by flash chromatography eluting with a 0–30% gradient ofacetone/CH₂Cl₂ to give the title compound.

Yield: 24% ¹H NMR Spectrum (DMSOd₆): 3.69 (s, 3H); 3.74 (s, 3H); 5.02(s, 2H); 6.8–6.93 (m, 3H); 6.95–7.08 (m, 2H); 7.12 (d, 1H); 7.28 (s,1H); 7.30 (d, 1H); 7.88 (s, 1H); 11.36 (s, 1H). MS-ESI: 327 [M+H]⁺

The starting material was prepared as follows:

2-Carbamoyl-5-hydroxy-1H-indole

A solution of 44 (1 g; 3.35 mmol) in Methanol (60 ml) was hydrogenatedunder medium pressure (45 psi) over 10% palladium on carbon (0.5 g) for2 hours. After filtration of the catalyst on celite, the filtrate wasevaporated to dryness to give 42 which was used without furtherpurification.

Yield: 95% ¹H NMR Spectrum (DMSOd₆): 6.71–6.74 (m, 1H); 6.8–6.95 (m,2H); 7.1–7.3 (m, 2H); 7.83 (broad, 1H); 8.78 (broad, 1H); 11.21 (s, 1H).

EXAMPLE 21

A solution of chlorosulfonyl isocyanate (0.365 ml; 4.2 mmol) inacetonitrile (1.5 ml) was added at 0° C. to a solution of 45 (1.2 g; 4.2mmol) in acetonitrile (12 ml). The mixture was stirred under argonatmosphere for 1 hour at 0° C. A solution of triethylamine (0.571 ml) inacetonitrile (3 ml) was then added at 0° C.; the mixture was allowed towarm up and stirred at room temperature for 3 hours. After evaporationthe residue was taken up in CH₂Cl₂. The organic phase was washed withdiluted NaHCO₃, evaporated and purified by flash chromatography elutingwith CH₂Cl₂ to give the title compound.

Yield: 52% MS-ESI: 311 [M+H]⁺

¹H NMR Spectrum (DMSOd₆): 3.72 (s, 3H); 3.77 (s, 3H); 6.93–7.023 (m,3H); 7.22 (d, 1H); 7.53 (m, 2H); 8.28 (s, 1H); 12.0 (s, 1H).

The starting material was prepared as follows

2-Methyl-4-(3,4-dimethoxyphenylsulphanyl)-nitrobenzene

To a solution of 46 (3.4 g; 20 mmol) and 47 (3.10 g; 30 mmol) in NMP (40ml) was added K₂CO₃ (4.14 g; 30 mmol). The mixture was stirred at 80° C.for 2 hours under argon atmosphere. After extraction with a mixture ofEther/Ethylacetate, the organic phase was evaporated and purified byflash chromatography, eluting with petroleum ether and petroleumether/ethylacetate 7:3 to give 48.

Yield: 83% ¹H NMR Spectrum (DMSOd₆): 2.48 (s, 3H); 3.74 (s, 3H); 3.77(s, 3H); 6.97 (dd, 1H); 7.10–7.20 (m, 4H); 7.9 (d, 1H).

2-(pyrrolidine-1-ylpropanyl-2-ylidene-4-(3,4-dimethoxyphenylsulphanyl)-nitrobenzene

To a solution of 48 (5.1 g; 16.7 mmol) in DMF (9 ml) was addedN,N-dimethylformamide dimethylacetal (2.57 ml; 19.3 mmol) andpyrrolidine (1.61 ml; 19.3 mmol). The mixture was heated at reflux underargon atmosphere for 3 hours. After extraction with AcOEt, the organicphase was evaporated to give 49 which was used in the next step withoutpurification.

Yield: 92%.

5-(3,4-Dimethoxyphenylsulphanyl)-1H-indole

To a solution of 49 (5.9 g; 15.2 mmol) in MeOH/THF (30 ml/30 ml) wasadded Raney Nickel (3 g). The mixture was heated at 48° C., under argonatmosphere and a solution of hydrazine hydrate (1.52 g; 30.4 mmol) inTHF/MeOH 30 ml/30 ml was added dropwise. After heating at 48° C. for 2hours, the mixture was filtered on celite. The filtrate was evaporatedand purified by flash chromatography eluting with AcOEt/petroleum ether30/70 to give 45.

Yield: 35% ¹H NMR Spectrum: 3.69 (s, 3H); 3.73 (s, 3H); 6.43 (s, 1H);6.77 (dd, 1H); 6.90–6.92 (m, 2H); 7.11 (dd, 1H); 7.39 (m, 2H); 7.64 (s,1H); 11.25 (s, 1H).

EXAMPLE 22 1-Methyl-3-cyano-5-(3,4-dimethoxyphenylsulphanyl)-1H-indole

To a solution of Example 21 (0.2 g; 0.64 mmol) in DMF (0.8 ml) at 0° C.was added NaH (0.03 g; 0.64 mmol) and CH₃I (0.06 ml; 0.64 mmol). Themixture was stirred at ambient temperature for 2 hours. After extractionwith AcOEt the organic phase was evaporated and purified by flashchromatography eluting with petroleum ether/AcOEt 60/40 to give thetitle compound.

Yield: 77% ¹H NMR Spectrum (DMSOd₆): 3.72 (s, 3H); 3.77 (s, 3H); 3.87(s, 3H); 6.98–7.03 (m, 3H); 7.30 (dd, 1H); 7.52 (s, 1H); 7.63 (d, 1H);8.28 (s, 1H). MS-ESI: 325 [M+H]⁺

EXAMPLE 23 3-Cyano-5-(3,4-dimethoxyphenylsulphonyl)-1H-indole

To a solution of Example 21 (0.13 g; 0.42 mmol) in CH₂Cl₂ (10 ml) andCH₃CN (2 ml) was added a solution of MCPBA (0.19 g; 0.88 mmol) inchloroform (5 ml). The mixture was heated at ambient temperature for onehour. After evaporation to dryness, the solid was triturated in etherand dried to give the title compound.

Yield: 59% ¹H NMR (DMSOd₆): 3.82 (s, 3H); 3.84 (s, 3H); 7.15 (d, 1H);7.45 (d, 1H); 7.61 (dd, 1H); 7.73 (d, 1H); 7.81 (dd, 1H); 8.25 (s, 1H);8.48 (s, 1H). MS-ESI: 341 [M−H]⁻

EXAMPLE 24 1-Methyl-3-cyano-5-(3,4-dimethoxyphenylsulphonyl)-1H-indole

The compound was prepared following the method described for example 23but starting with compound of example 22.

Yield: 77%. ¹H NMR (DMSOd₆): 3.78 (s, 3H); 3.82 (s, 3H); 3.91 (s, 3H);7.13 (d, 1H); 7.46 (s, 1H); 7.60 (dd, 1H); 7.84–7.91 (m, 2H); 8.25 (s,1H); 8.48 (s, 1H). MS-ESI: 357 [M+H]⁺

1. A compound of Formula (VIId),

wherein R¹ is independently selected from hydroxy, amino, alkanoylamino,—OPO₃H₂, or C₁₋₄alkoxy, wherein the amino group is optionallysubstituted with an amino acid residue and the hydroxy group isoptionally esterified; X is selected from —O—, —S—, —SO—, or —SO₂—; R²is selected from hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy; R⁴ is independentlyselected from hydrogen, C₁₋₄alkyl, ₁₋₄alkanoyl, C₁₋₄alkoxycarbonyl,C₁₋₄alkoxycarbonylC₁₋₄alkyl, aminoC₁₋₄alkyl, carbamoyl,carbamoylC₁₋₄alkyl, cyano, cyanoC₁₋₄alkyl, hydroxy or hydroxyC₁₋₄alkyl;R⁵ is selected from hydrogen, C₁₋₄alkyl, or a group of Formula (III)

wherein Y is selected from —NH—, —O—, or a bond; Z is selected from—NH—, —O—, —C(O)— or a bond; r is an integer from 0 to 4; t is aninteger from 0 to 1; R⁸ is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy, aryl, 5- or6-membered heterocyclyl, 5- or 6-membered heteroaryl, wherein aryl,heteroaryl or heterocyclyl are optionally substituted with C₁₋₄alkyl,C₁₋₄alkoxy, or a group of Formula (IV)

wherein n is an integer from 1 to 6, and; R⁹ and R¹⁰ are independentlyselected from hydrogen, C₁₋₄alkyl or aryl; p is an integer from 0 to 1and q is an integer from 1 to 3; or a salt, or solvate thereof.
 2. Acompound of claim 1, selected from:3-cyano-5-(4-hydroxyphenoxy)-1H-indole; and1-methyl-3-cyano-5-(4-hydroxy-3,5-dimethoxyphenoxy)-1H-indole;1-methyl-3-cyano-5-(4-phosphonoxy-3,5-dimethoxyphenoxy)-1H-indole;3-cyano-5-(3,4-dimethoxyphenylsulphanyl)-1H-indole;1-methyl-3-cyano-5-(3,4-dimethoxyphenylsulphanyl)-1H-indole;3-cyano-5-(3,4-dimethoxyphenylsulphonyl)-1H-indole; and1-methyl-3-cyano-5-(3,4-dimethoxyphenylsulphonyl)-1H-indole; or salt, orsolvate thereof.
 3. A compound according to claim 1 wherein X is —O—. 4.A compound according to claim 1 wherein X is —S—, —SO—or —SO₂—.
 5. Acompound according to claim 1 wherein R¹ is selected from hydroxy,amino, —OPO₃H₂, methoxy, ethoxy, glutamylamino, α-glutamylamino,serylamino, glycylamino and alanylamino.
 6. A compound according toclaim 1 wherein R¹ is selected from hydroxy, α-glutamylamino, seryl,—OPO₃H² or methoxy.
 7. A compound according to claim 1 wherein q is 2 or3.
 8. A compound according to claim 1 wherein R² is hydrogen.
 9. Acompound according to claim 1 wherein R⁴ is hydrogen, cyano, carbamoyl,carbamoylC₁₋₄alkyl or C₁₋₄alkoxycarbonyl.
 10. A compound according toclaim 1 wherein R⁵ is hydrogen or C₁₋₄alkyl.
 11. A compound according toclaim 1 wherein R⁵ is hydrogen, methyl or ethyl.
 12. A pharmaceuticalcomposition comprising a compound according to any one of claims 1, 2, 3to 11 or a pharmaceutically acceptable salt, or solvate or thereof. 13.A process for preparing a compound of claim 1, or salt, or solvatethereof, comprising a) for compounds of Formula (I) wherein X is —O— or—S—, reacting a compound of Formula (A) with a compound of Formula (B),

wherein L¹ is a leaving group; b) for compounds of Formula (I) in whichR⁻ is amino, reduction of a compound of Formula (C):

c) for compounds of Formula (I) wherein R⁵ is C₁₋₄alkyl, reacting acompound of Formula (I) wherein R⁵ is hydrogen with a suitablealkylhalide; d) for compounds of Formula (I) wherein R¹ comprises anamino group substituted with an amino acid residue, reacting a compoundof Formula (D) with an amino acid,

e) for compounds of Formula (I) in which R⁴ is hydrogen, reactingcompounds of Formula (I) in which R³ is hydrogen and R⁴ is hydrogen withcompounds of L³R³ in which L³ is a leaving group ; and f) for compoundsof Formula (I) in which R¹ is an esterified hydroxyl group, reacting acompound of Formula (F) with ar appropriate carboxylic acid orcarboxylic acid derivative;

and thereafter optionally i) converting a compound of Formula (I) intoanother compound of Formula (I); ii) removing any protecting groups;iii) forming a salt, or solvate.